Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997–2025): trends and future directions

Abstract

Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.

Graphical Abstract

Introduction

Neurological and psychiatric disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia, and depression, are major public health challenges, affecting millions globally [1]. These conditions are marked by complex and multifactorial pathophysiologies, including neuroinflammation, oxidative stress, protein aggregation, neurotransmitter imbalances, and neurodegeneration [2]. The interplay between genetic, environmental, and biochemical factors often exacerbates the disease progression, leading to irreversible damage and long-term disability. Despite progress in pharmaceutical interventions, current treatments are limited by poor bioavailability, side effects, and their inability to address the underlying disease mechanisms, underscoring the urgent need for novel therapeutic approaches.

Nanotechnology has emerged as a transformative avenue in the treatment of neurological and psychiatric disorders [3, 4]. Nanomaterials, including nanoparticles, nanocarriers, nanocomposites, cubosomal systems, and solid lipid nanoparticles, offer unique physicochemical properties that enable targeted drug delivery, imaging, and theranostic interventions [5, 6]. Their ability to cross biological barriers, particularly the blood–brain barrier (BBB), and interact with disease-specific mechanisms at the molecular and cellular levels opens new avenues for more effective treatments [7–10]. In addition, nanomaterials can be engineered to alleviate oxidative stress, reduce neuroinflammation, and target misfolded proteins, offering the potential for precision therapies with fewer side effects.

This review aims to provide an in-depth exploration of the current state of nanomaterials in the treatment of neurological and psychiatric disorders, focusing on their ability to target specific disease mechanisms. We begin by reviewing the pathogenesis of these disorders to highlight the molecular alterations involved, followed by an analysis of how nanomaterials can be used to intervene in these processes. The review examines various nanomaterial-based therapies, from nanoparticles to nanostructures, and their roles in managing conditions such as AD, PD, and schizophrenia (Scheme 1). Despite the promising advancements, challenges such as biocompatibility, targeted delivery, and scalability remain, and these are discussed in detail. Finally, we identify future research directions to optimize the use of nanomaterials in clinical settings and improve therapeutic outcomes. Through this review, we aim to emphasize the transformative potential of nanomaterials in advancing the treatment of neurological and psychiatric disorders.

Scheme 1:

Nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders. (By Figdraw)

Methodology

Sources of data and search strategy

All data were retrieved and downloaded from the Web of Science Core Collection database (WOS, www.webofknowledge.com).

The inclusion criteria were set as follows:

(1) search terms TS = (“nanomaterials” OR “nanoparticles” OR “nanocarriers” OR “nano-therapy” OR “nano-drug delivery”) AND (“Parkinson’s disease” OR “Alzheimer’s disease” OR “Huntington’s disease” OR “depression” OR “schizophrenia” OR “ischemic stroke” OR “insomnia” OR “autism” OR “epilepsy”) AND (“treatment” OR “therapy” OR “drug delivery” OR “neuroprotection” OR “neurotherapeutics” OR “biomedical applications”).

(2) document type limited to “Article” and “Review Article”;

(3) publication date ranged from January 1997 to August 2025. Exclusion criteria comprised: Early Access, Meeting Abstract, Proceeding Paper, Retracted Publication, Editorial Material, Book Chapters, Letter, Correction, Retraction and Publication With Expression Of Concern (Fig. 1).

Fig. 1.

Screening flowchart

Data analysis

First, basic information from the records was extracted, including article titles, authors, publication years, abstracts, keywords, citation counts, and categorized. Quantitative and visual analyses were conducted using Microsoft Excel (version 16.62), VOSviewer (version 1.6.20), CiteSpace (version 6.4.R1), and the R package “bibliometrix” (https://www.bibliometrix.org). The latest Impact Factors (IF) and Journal Citation Reports (JCR) quartiles were retrieved from the official WOS platform. In VOSviewer, co-authorship and co-citation network analyses were performed with a minimum document threshold of 5 publications per author and a minimum citation threshold of 10 per source; the full-counting method was applied for link-strength normalization. In CiteSpace, the analysis was configured with a time slicing of one year per slice, and both burst detection and cluster analysis were performed using default Kleinberg’s burst detection algorithm with Pathfinder pruning. In R-Bibliometrix, the annual compound growth rate (ACGR) of publications was calculated to quantify the field’s expansion trend. Deduplication was performed automatically by the WoS export function; records with identical titles and authors across multiple database editions were manually verified and removed. The complete Boolean search string employed was: TS = (“nanomaterials” OR “nanoparticles” OR “nanocarriers” OR “nano-therapy” OR “nano-drug delivery”) AND (“Parkinson’s disease” OR “Alzheimer’s disease” OR “Huntington’s disease” OR “depression” OR “schizophrenia” OR “ischemic stroke” OR “insomnia” OR “autism” OR “epilepsy”) AND (“treatment” OR “therapy” OR “drug delivery” OR “neuroprotection” OR “neurotherapeutics” OR “biomedical applications”), restricted to Articles and Review Articles in English published from January 1997 to August 2025.

Results

Quantitative analysis of publications

To ensure the authority of the original literature, this study selected the internationally recognized WOS database as the data source. By refining “document types” and “languages”, literature that did not meet the study criteria was excluded, retaining original articles adhering to the search criteria. From January 1997 to August 2025, a total of 3,987 articles were published, with an annual publication volume showing a consistent upward trend (Fig. 2A). The total number of articles is projected to reach a new milestone by the end of 2025. Bibliometric analysis of disease-specific publication distribution reveals that neurological conditions account for the overwhelming majority of the literature: Alzheimer’s disease (AD) contributed the largest share (approximately 28%), followed by Parkinson’s disease (PD, ~ 22%), ischemic stroke (~ 15%), epilepsy (~ 10%), and Huntington’s disease (~ 5%). In contrast, psychiatric conditions including depression (~ 8%), schizophrenia (~ 5%), autism spectrum disorder (~ 4%), and insomnia (~ 3%) collectively represented a substantially smaller proportion of publications. This asymmetry is itself a meaningful bibliometric finding: the greater research momentum in neurological nanomedicine reflects both the longer history of these conditions as therapeutic targets and the more established preclinical models available for neurodegenerative diseases. Nonetheless, the comparatively lower volume of psychiatric nanomedicine research identifies a critical underrepresented domain, and we have accordingly expanded our coverage of psychiatric conditions throughout this review to reflect their growing importance.

Fig. 2.

A Statistical chart of publications from January 1997 to August 2025, B Geographic map of country collaboration networks, C Country collaboration network diagram, D Comparative analysis of single-country and multi-country collaborative publications, E Top 20 most productive institutions, F Institutional co-authorship network diagram

Countries and institutions

Research on nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders has gained significant global attention, with studies conducted in 75 countries worldwide (Fig. 2B). These include 29 countries in Asia, 28 in Europe, 9 in Africa, 4 in South America, 3 in North America, and 2 in Oceania, highlighting the growing international interest in this field. Among these, Asian countries (n = 4), European countries (n = 3), North American countries (n = 1), African countries (n = 1), and South American countries (n = 1) dominate the top 10 regions based on the total number of publications (Table 1). China leads with 1,421 published articles, followed by India (n = 604) and the United States (n = 294). A collaboration network among the top 50 countries by total publications was visualized (Fig. 2C), revealing active international partnerships. For instance, China collaborates closely with the USA, India, Saudi Arabia, and Egypt, while the USA forms partnerships with Italy, India, Germany, and others. Notably, China not only ranks first in total publications but also leads in both single-country and multi-country collaborative publications (Fig. 2D).

Table 1.

Top 20 countries and institutions by total publication volume

Rank	Country	Counts	Rank	Affiliation	Articles
1	China (Asia)	1421(35.6%)	1	Egyptian Knowledge Bank, EKB (Egypt)	431(2.64%)
2	India (Asia)	604(15.1%)	2	Chinese Academy of Sciences (China)	344(2.11%)
3	USA (North America)	294(7.4%)	3	Fudan University (China)	173(1.06%)
4	Iran (Asia)	195(4.9%)	4	Shanghai Jiao Tong University (China)	134(0.82%)
5	Egypt (Africa)	136(3.4%)	5	Sichuan University (China)	132(0.81%)
6	Italy (Europe)	122(3.1%)	6	Zhejiang University (China)	118(0.72%)
7	Korea (Asia)	119(3%)	7	Jamia Hamdard University (India)	117(0.72%)
8	Spain (Europe)	95(2.4%)	8	Sun Yat Sen University (China)	110(0.67%)
9	Brazil (South America)	86(2.2%)	9	King Abdulaziz University (Saudi Arabia)	96(0.59%)
10	Portugal (Europe)	73(1.8%)	10	Tehran University of Medical Sciences (Iran)	93(0.57%)
11	United Kingdom (Europe)	62(1.6%)	11	University of Chinese Academy of Sciences, CAS (China)	93(0.57%)
12	Saudi Arabia (Asia)	60(1.5%)	12	Universidade De Coimbra (Portugal)	92(0.56%)
13	Canada (North America)	50(1.3%)	13	UPORTO Universidade do Porto (Portugal)	91(0.56%)
14	Australia (Oceania)	44(1.1%)	14	Tianjin University (China)	89(0.54%)
15	Germany (Europe)	39(1%)	15	University of Barcelona (Spain)	86(0.53%)
16	Poland (Europe)	39(1%)	16	National Institute of Pharmaceutical Education and Research (India)	71(0.43%)
17	France (Europe)	36(0.9%)	17	Changchun Institute of Applied Chemistry, CAS (China)	68(0.42%)
18	Pakistan (Asia)	35(0.9%)	18	Mashhad University of Medical Sciences (Iran)	67(0.41%)
19	Mexico (North America)	34(0.9%)	19	Cairo University (Egypt)	63(0.39%)
20	Japan (Asia)	33(0.8%)	20	Zhengzhou University (China)	63(0.39%)

Research on nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders has been conducted across 2,624 research institutions worldwide. Among these, the top 10 institutions are distributed across five countries (Fig. 2E, Table 1): China (n = 6), Egypt (n = 1), Saudi Arabia (n = 1), India (n = 1), and Iran (n = 1). The three institutions with the highest number of relevant publications are the Egyptian Knowledge Bank (431 publications, 2.64%), the Chinese Academy of Sciences (344 publications, 2.11%), and Fudan University (173 publications, 1.06%). It should be noted that the anomalously high publication count attributed to the Egyptian Knowledge Bank (EKB) is likely a consequence of affiliation parsing artifacts in the WoS database, as EKB is a national subscription and access platform rather than a research-producing institution per se; this ranking should therefore be interpreted with appropriate caution. Additionally, a total of 36 institutions, each with ≥ 50 publications, were included in the collaboration network analysis (Fig. 2F). The Chinese Academy of Sciences has established strong collaborative links with institutions such as Shanghai Jiao Tong University, Fudan University, and University of Chinese Academy of Sciences.

Journals and co-cited journals

Globally, a total of 791 journals have published papers on nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders. Among these, Pharmaceutics ranked first in publication volume (n = 117, 2.93%), followed by Journal of Drug Delivery Science and Technology (n = 110, 2.76%). Within the top 20 journals by publication volume (Fig. 3A and Table 2), Biomaterials had the highest impact factor (IF = 12.9), with Journal of Nanobiotechnology (IF = 12.6) ranking second. Subsequently, journals with a minimum publication count of 20 articles were selected, resulting in 46 journals used to construct a journal co-citation network (Fig. 3B). The analysis revealed active citation relationships among Journal of Controlled Release, Pharmaceutics, International Journal of Nanomedicine, Small, ACS Nano, and Nanoscale.

Fig. 3.

A Top 20 journals by publication volume, B Journal co-publication network, C Top 20 journals by citation count, D Journal co-citation network diagram, E Dual-map overlay of research journals

Table 2.

Top 20 journals by number of publications

Rank	Sources	Articles	IF	Country/Region	JCR
1	Pharmaceutics	117(2.93%)	5.5	Switzerland	Q1
2	Journal of drug delivery science and technology	110(2.76%)	4.9	France	Q1
3	International journal of nanomedicine	88(2.21%)	6.5	New Zealand	Q2
4	Journal of controlled release	87(2.2%)	11.5	Netherlands	Q1
5	International journal of pharmaceutics	84(2.13%)	5.2	Netherlands	Q2
6	International journal of molecular sciences	74(1.86%)	4.9	United States	Q1
7	ACS applied materials & interfaces	73(1.83%)	8.2	United States	Q1
8	Biomaterials	70(1.76%)	12.9	Netherlands	Q1
9	International journal of biological macromolecules	65(1.63%)	8.5	Netherlands	Q1
10	ACS nano	61(1.53%)	16	United States	Q1
11	Journal of nanobiotechnology	52(1.3%)	12.6	England	Q1
12	Nanomedicine-nanotechnology biology and medicine	47(1.18%)	4.6	Netherlands	Q2
13	Current pharmaceutical design	45(1.13%)	2.8	Netherlands	Q2
14	Molecules	40(1%)	4.6	Switzerland	Q2
15	Small	40(1%)	12.1	Germany	Q1
16	Colloids and surfaces B-biointerfaces	38(0.95%)	5.6	Netherlands	Q1
17	Nanomedicine	38(0.95%)	3.9	England	Q2
18	Advanced healthcare materials	37(0.93%)	9.6	Germany	Q1
19	Journal of materials chemistry B	37(0.93%)	5.7	England	Q1
20	Scientific reports	36(0.9%)	3.9	England	Q1

Among the top 20 journals ranked by co-citation frequency (Table 3 and Fig. 3C), three journals exceeded 5,000 co-citations. Journal of Controlled Release had the highest co-citation count (n = 8162), followed by Biomaterials (n = 6196), and International Journal of Pharmaceutics (n = 5747). Journals with a minimum co-citation count of 1000 were selected, resulting in 66 highly cited journals used to construct a co-citation network (Fig. 3D). The analysis revealed significant co-citation relationships between Journal of Controlled Release and journals such as Biomaterials and International Journal of Nanomedicine. Dual-map overlay of journals revealed that studies published in Chemistry/Materials/Physics, and Molecular/Biology/Genetics journals were primarily cited by literature from Physics/Materials/Chemistry journals, and Molecular/Biology/Immunology (Fig. 3E).

Table 3.

Top 20 co-cited journals

Rank	Sources	Articles	IF	Country/Region	JCR
1	Journal of controlled release	8162	11.5	Netherlands	Q1
2	Biomaterials	6196	12.9	Netherlands	Q1
3	International journal of pharmaceutics	5747	5.2	Netherlands	Q2
4	ACS nano	4830	16	United States	Q1
5	International journal of nanomedicine	4093	6.5	New Zealand	Q2
6	Proceedings of the national academy of sciences	3590	9.1	United States	Q1
7	International journal of molecular sciences	3324	4.9	United States	Q1
8	Advanced drug delivery reviews	3299	17.6	Netherlands	Q1
9	Pharmaceutics	2946	5.5	Switzerland	Q1
10	Scientific reports	2833	3.9	England	Q1
11	Advanced materials	2785	27.4	United States	Q1
12	ACS applied materials & interfaces	2768	8.2	United States	Q1
13	PLOS ONE	2685	2.6	United States	Q2
14	Nature	2487	50.5	England	Q1
15	Journal of the american chemical society	2342	14.5	United States	Q1
16	Journal of biological chemistry	2218	3.9	United States	Q2
17	Nanomedicine-nanotechnology	2210	4.6	Netherlands	Q2
18	European journal of pharmaceutics and biopharmaceutics	2194	4.3	Netherlands	Q1
19	Colloids and surfaces B-biointerfaces	2186	5.6	Netherlands	Q1
20	Science	2182	45.8	United States	Q1

Authors and co-cited authors

A total of 16,802 authors have published papers in the field of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders, with an average of 6.92 authors per paper. Among the top 20 authors ranked by publication volume (Table 4 and Fig. 4A), four authors (WANG Y, LIU Y, LIU J, and ZHANG Y) exceeded 50 total publications, and they exhibited the largest nodes in the visual network analysis diagram (Fig. 4B). Additionally, QU XG demonstrated close collaborations with REN JS, WANG Y, and other authors. LIU Y and ZHANG Y achieved the highest H-index of 29 (Fig. 4C), surpassing other authors, and their publications were predominantly concentrated from 2010 onwards (Fig. 4D).

Table 4.

Top 20 authors and co-cited authors

Rank	Author	Articles	Rank	Author	Co-citations
1	WANG Y	74	1	LIU J	818
2	LIU Y	64	2	ALI J	736
3	LIU J	53	3	BABOOTA S	706
4	ZHANG Y	51	4	QU XG	647
5	LI Y	47	5	REN JS	601
6	ALI J	39	6	LIU Y	576
7	ZHANG L	37	7	ZHANG Y	523
8	BABOOTA S	36	8	SAHNI JK	511
9	LI J	35	9	MD S	503
10	WANG J	35	10	JIANG XG	472
11	SUN Y	34	11	WANG Y	466
12	ZHANG H	33	12	LI M	456
13	CHEN Y	31	13	ZHANG QZ	436
14	ZHANG X	31	14	LI Y	417
15	DONG XY	30	15	JIANG C	401
16	QU XG	30	16	CHEN J	382
17	WANG H	29	17	RE F	366
18	REN JS	28	18	SARAF S	366
19	WANG C	26	19	GUO Q	352
20	ZHANG J	26	20	ZHANG C	349

Fig. 4.

A Top authors by publication volume, B Author collaboration network, C Authors’ H-indices, D Temporal distribution of authors’ publications, E Top authors by citation count, F Co-citation network of cited authors

Co-cited authors refer to authors whose works are cited together by one or multiple other publications, thereby establishing co-citation relationships. Citation count serves as a key metric for evaluating author contributions. LIU J emerged the most frequently cited one (Fig. 4E and Table 4). From the 16,802 co-cited authors, 74 authors with citation counts exceeding 200 were selected for co-citation network mapping, which revealed active collaboration among distinct co-authors (Fig. 4F).

Literature and co-cited references

Among the 3,987 research articles on nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders, the global total citation count reached 135,811. The top 10 globally cited publications were published in Journal of Controlled Release (n = 2), NPG Asia Materials (n = 1), Nanomedicine-Nanotechnology (n = 1), Theranostics (n = 1), Molecules (n = 1), Angewandte Chemie International Edition (n = 1), ACS NANO (n = 1), Journal of the American Chemical Society (n = 1), and Advanced Materials (n = 1). Notably, “Cláudia Saraiva., et al. Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases. Journal of Controlled Release, 2016(235), 34–47.” [11] is the most cited paper in this field to date, with a total citation count of 1075, followed by “Xu, C., et al. Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Mater. 2014(6), e90 [12]” and “Chen, J., et al. Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nature Nanotech. 2006(1), 142–150 [13]” (Table 5).

Table 5.

Top 20 globally highly cited publications

Rank	Paper	DOI	Total citations	TC per year	Normalized TC
1	SARAIVA C, 2016, J CONTROL RELEASE	10.1016/j.jconrel.2016.05.044	1075	107.50	17.82
2	XU C, 2014, NPG ASIA MATER	10.1038/am.2013.88	925	77.08	12.40
3	CHEN JP, 2006, NAT NANOTECHNOL	10.1038/nnano.2006.91	770	38.50	4.26
4	DONG XW, 2018, THERANOSTICS	10.7150/thno.21254	689	86.13	10.83
5	BASNET P, 2011, MOLECULES	10.3390/molecules16064567	565	37.67	6.19
6	SINGH N, 2017, ANGEW CHEM INT EDIT	10.1002/anie.201708573	562	62.44	8.99
7	BAO XF, 2018, ACS NANO	10.1021/acsnano.8b04022	556	69.50	8.74
8	CABALEIRO-LAGO C, 2008, J AM CHEM SOC	10.1021/ja8041806	478	26.56	4.47
9	LI M, 2012, ADV MATER	10.1002/adma.201104864	477	34.07	4.96
10	LIU YL, 2017, J AM CHEM SOC	10.1021/jacs.6b11013	468	52.00	7.49
11	CROISSANT JG, 2018, ADV HEALTHC MATER	10.1002/adhm.201700831	465	58.13	7.31
12	AGRAWAL M, 2018, J CONTROL RELEASE	10.1016/j.jconrel.2018.05.011	455	56.88	7.15
13	MANCUSO C, 2014, FOOD CHEM TOXICOL	10.1016/j.fct.2013.12.024	443	36.92	5.94
14	SINGH AP, 2019, SIGNAL TRANSDUCT TAR	10.1038/s41392-019-0068-3	442	63.14	7.84
15	MARRACHE S, 2012, P NATL ACAD SCI USA	10.1073/pnas.1210096109	412	29.43	4.29
16	LAMPTEY RNL, 2022, INT J MOL SCI	10.3390/ijms23031851	412	103.00	15.33
17	TAPEINOS C, 2017, J CONTROL RELEASE	10.1016/j.jconrel.2017.08.033	408	45.33	6.53
18	WEINSTEIN JS, 2010, J CEREBR BLOOD F MET	10.1038/jcbfm.2009.192	397	24.81	3.74
19	WONG HL, 2012, ADV DRUG DELIVER REV	10.1016/j.addr.2011.10.007	392	28.00	4.08
20	MUSUMECI T, 2006, INT J PHARMACEUT	10.1016/j.ijpharm.2006.06.023	370	18.50	2.05

Research focus

By examining keyword bursts, one can identify the research hotspots, trends, and evolving dynamics of nanomaterial research in the diagnosis and treatment of neurological and psychiatric disorders. The top 25 keywords with the strongest citation bursts are displayed in the Fig. 5. The red lines represent the time periods of citation bursts. The keyword “in vivo” shows the highest citation burst, with a strength of 10.08 (2015–2018). Other keywords that experienced significant citation bursts include “controlled release” (S/8.15), “nasal drug delivery” (S/5.04), “cytotoxicity” (S/4.42), and “magnetic nanoparticles” (S/9.03).

Fig. 5.

Top 25 Keywords with the strongest citation bursts

In terms of duration, keywords such as “magnetic nanoparticles”, “oligomers”, and “doxorubicin” maintained significant citation bursts from 2015 to 2019. Notably, the field’s ongoing trend is evident in the recent surge of keywords such as “nerve growth factor”, “cognitive deficits”, “alzheimer’s disease”, and “targeted therapy”, which reflect the increasing focus on medical applications, particularly in diagnosis and treatment. Citation burst analysis reveals a shift in focus; up until around 2017, research in this field mainly concentrated on fundamental studies such as enzyme-like activity and nanoparticle synthesis. After 2018, the emphasis gradually shifted towards the design and clinical application areas, including diagnostics, therapy, and targeted delivery systems.

Based on the evaluation of high-frequency keywords and their clustering analysis, the main research directions in nanomaterials primarily include the exploration of new activities, materials, design strategies, catalytic mechanisms, and biomedical applications. These findings highlight the significant potential of nanomaterials, especially their unique properties and enhanced catalytic efficiency, across a range of scientific disciplines. As this review progresses, we will categorize therapeutic strategies for neurological and psychiatric disorders according to their underlying mechanisms and explore how nanomaterials are driving innovations in the diagnosis and treatment of these complex conditions.

Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by progressive dopaminergic neuronal loss in the substantia nigra together with abnormal α-synuclein (α-syn) aggregation [14]. Although current therapies, including dopamine replacement and deep brain stimulation, can alleviate motor symptoms, they do not halt disease progression [15–17]. From the perspective of nanotherapeutic intervention, the most actionable mechanisms in PD are α-syn dysregulation and propagation, mitochondrial dysfunction, lysosomal impairment, oxidative stress, and neuroinflammation (Fig. 6 and Table 6) [18]. These interconnected pathological nodes provide the main biological rationale for the nanomaterial-based strategies discussed below.

Fig. 6.

Molecular Mechanisms in PD Pathogenesis. A–F Reproduced with permission from ref [18].

Copyright 2024, Elsevier

Table 6.

Major mechanisms of PD pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Genetic factors	Dysregulation of SNCA, LRRK2, VPS35, and GBA1 genes leads to altered protein aggregation, dysfunctional cellular processes, and abnormal α-syn accumulation	Increased α-syn aggregation leads to cellular dysfunction, neurodegeneration, and the formation of Lewy bodies, contributing to the pathogenesis of PD	Targeting α-syn aggregation, modulating gene expression related to SNCA, LRRK2, VPS35, and GBA1 to restore cellular homeostasis and prevent protein aggregation
Neuropathological changes	Increased aggregation of α-syn in neurons forms Lewy bodies, causing neuronal toxicity and dysfunction. α-syn propagation spreads the pathology across the CNS	Propagation of α-syn pathology throughout the nervous system leads to progressive neurodegeneration and impaired brain function	Developing strategies to inhibit or slow the propagation of α-syn pathology, and targeting the early-stage oligomeric species as potential therapeutic targets
Abnormal molecular mechanisms	Mitochondrial dysfunction, impaired mitophagy, and lysosomal dysfunction contribute to oxidative stress and protein aggregation. Abnormal cellular transport via LRRK2 and VPS35 further exacerbates neuronal damage	Mitochondrial dysfunction and lysosomal impairment drive oxidative stress and neuronal death, worsening disease progression. Disruption in intracellular transport further destabilizes cellular homeostasis	Developing mitochondrial-targeted therapies, enhancing mitophagy (via PINK1, PRKN) and restoring lysosomal function to reduce oxidative damage and prevent neuronal death
Immune and inflammatory mechanisms	Activation of microglia and increased cytokine levels in the CNS, along with abnormal α-syn aggregation, induces both innate and adaptive immune responses, causing neuroinflammation	Chronic neuroinflammation driven by microglial activation and immune response triggers neurodegeneration, exacerbating PD symptoms and progression	Immunomodulatory therapies aimed at controlling microglial activation and regulating inflammatory cytokine levels in both the central and peripheral immune systems

(1) Genetic Factors

Genetic contributors to PD include SNCA, LRRK2, VPS35, and GBA1, which collectively regulate α-syn expression, intracellular trafficking, and lysosomal degradation [19–23]. Among these, SNCA dysregulation is particularly important because it directly promotes α-syn accumulation, whereas LRRK2, VPS35, and GBA1 mutations further exacerbate protein aggregation and cellular dysfunction by disturbing endosomal–lysosomal homeostasis [24–26]. These pathways are highly relevant to nanomedicine because they provide upstream targets for gene modulation and intracellular delivery strategies.

(2) Neuropathological Changes

A central pathological hallmark of PD is the accumulation of misfolded α-syn, which forms toxic oligomers, fibrils, Lewy bodies, and Lewy neurites [27–29]. In addition to intracellular toxicity, misfolded α-syn can propagate across neural systems through cell-to-cell transfer and extracellular vesicle-mediated spread [30–32]. Because these early oligomeric and propagative events are strongly linked to disease progression, they represent key targets for aggregation-disrupting and propagation-blocking nanoplatforms.

(3) Abnormal Molecular Mechanisms

Mitochondrial dysfunction, impaired mitophagy, lysosomal failure, and defective intracellular transport are major molecular drivers of PD progression [33–35]. These abnormalities promote ATP depletion, ROS overproduction, abnormal protein accumulation, and synaptic injury, thereby accelerating neuronal degeneration [36, 37]. From a nanotherapeutic perspective, these processes are especially important because they define opportunities for antioxidant, mitochondria-targeted, and lysosome-restoring nanomedicines.

(4) Immune and Inflammatory Mechanisms

Neuroinflammation in PD involves microglial activation, cytokine dysregulation, innate and adaptive immune responses, and, potentially, gut–brain immune interactions [38, 39]. Although early immune activation may initially support the clearance of abnormal proteins, persistent inflammation becomes neurotoxic and amplifies neuronal loss. This makes inflammatory regulation another major intervention axis for nanomaterial-based therapy.

These mechanisms do not act independently; rather, they converge to drive progressive neuronal dysfunction and provide the principal targets for PD-oriented nanotherapeutic design. With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Regulating SNCA expression via nanomaterials for PD treatment

Neurodegenerative diseases, such as PD, have a significant impact on human health. The complex pathological mechanisms underlying these diseases present considerable challenges for therapeutic interventions. Gene therapy has emerged as a promising strategy, relying on the intracellular delivery of nucleic acids. This approach functions through two main mechanisms: either by introducing functional genetic material to restore normal cellular processes or by selectively silencing pathogenic gene expression to precisely modulate cellular signaling pathways. However, gene-based therapies face inherent challenges, including structural instability and an anionic surface charge, both of which hinder their interaction with biological membranes and result in suboptimal transfection efficiency. Furthermore, gene-based drugs encounter substantial barriers during their delivery to the sites of neurodegenerative lesions, including the BBB and cell membrane barriers, which limit drug accumulation at the lesion site and reduce therapeutic efficacy [40].

Small interfering RNA (siRNA) targeting SNCA (siSNCA) holds promise for treating PD as it specifically downregulates α-syn protein expression, effectively curbing α-syn aggregate formation [41]. However, siSNCA alone is insufficient to directly mitigate the pathological conditions arising from elevated ROS levels. Ceria (CeO₂) nanozymes possess excellent ROS-scavenging capabilities. When incorporated onto nanocarriers, they enhance surface roughness, mimicking the nanoscale topography of certain neurotropic viruses, thus promoting cellular uptake. To leverage these insights, Zhang et al. [42] developed self-catalytic small interfering RNA (siRNA) nanocarriers (S/Ce-PABMS). These nanocarriers consist of superparamagnetic iron oxide nanoparticles (SPIONs) at their core, a middle layer composed of silica (SiO₂) and CeO₂ nanozymes, and a surface modification with polymers synthesized from 2-methacryloyloxyethyl phosphorylcholine (MPC) and phenylboronic acid-functionalized poly(2-aminoethyl methacrylate) (PAEMAB, abbreviated as PAB), which subsequently absorb siRNA (Fig. 7A). The MPC moiety, acting as an ACh analog, binds specifically to ACh receptors abundantly expressed in brain microvascular endothelial cells and neurons, enabling the S/Ce-PABMS to efficiently cross the BBB and accumulate in target neurons (Fig. 7B). Furthermore, the rough surface of the CeO₂ nanozyme-loaded nanocarriers generates nonspecific binding forces, synergistically enhancing cellular uptake efficiency upon receptor-mediated binding. Due to the significantly higher intracellular concentration of adenosine triphosphate (ATP) (approximately 4 × 10^–3 M) compared with the extracellular environment (< 0.4 × 10^–3 M), the high intracellular ATP levels trigger a reaction with the phenylboronic acid moiety, inducing a charge reversal on the nanocarrier surface. This electrostatic change promotes the release of siRNA into the cytoplasm. Following cytoplasmic release, siRNA associates with the RNA-induced silencing complex (RISC), undergoing unwinding into guide and passenger strands. The guide strand specifically binds to target SNCA mRNA, guiding endonuclease activity within RISC to cleave the mRNA and prevent translation, thus effectively suppressing α-syn expression and subsequent aggregation (Fig. 7C). Concurrently, the CeO₂ nanozymes effectively scavenge excess ROS (Fig. 7D), mitigating mitochondrial damage and further synergizing with siSNCA to reduce α-syn aggregates. This combined action also indirectly alleviates neuroinflammation by promoting anti-inflammatory interleukin-10 (IL-10) secretion while decreasing pro-inflammatory interleukin-1β (IL-1β) production. Upon intravenous administration, the S/Ce-PABMS displayed maximal concentration within dopaminergic neurons at 12 h post-injection, demonstrating effective brain targeting (Fig. 7E and F). Treatment with S/Ce-PABMS significantly reduced α-syn protein and aggregate levels, markedly decreased ROS, and significantly increased tyrosine hydroxylase (TH)-positive neuron numbers in PD model mice (Fig. 7G). Notably, these mice showed substantial improvements in motor coordination compared with controls. In conclusion, S/Ce-PABMS represents a highly promising therapeutic strategy for PD, offering considerable potential for future clinical translation.

Fig. 7.

A Schematic representation of S/Ce-PABMS in the treatment of PD, B Bioluminescence imaging of detected siRNA, C Western blot analysis of α-syn protein expression, D Measurement of ROS levels, E Fluorescence imaging to observe S/Ce-PABMS interactions, F Representative images of TH staining in PD model tissues, G Quantification of α-syn aggregates, H Schematic diagram of ZnO@Polymer-NpG for PD treatment, I Fluorescent spectrum of ZnO@Polymer-NpG at pH 5.5 and pH 7.4; J Electrophoresis results of ZnO@Polymer-NpG at pH 5.5 and pH 7.4, K Western blotting analysis of SNCA expression, L Ex vivo fluorescence imaging of treated tissues; M Schematic diagram of RVG-CRISPRi-Exo for gene modulation in PD, N Cellular uptake of CRISPRi-Exo and RVG-CRISPRi-Exo, O Western blot analysis of α-syn protein levels, P Representative fluorescence images of CRISPRi-Exo and RVG-CRISPRi-Exo, Q Quantitative analysis of α-syn expression changes, R PET imaging to evaluate synaptic function and neurodegeneration. A–G Reproduced with permission from ref [42].

Copyright 2022, Wiley. H–L Reproduced with permission from ref [43]. Copyright 2022, Elsevier. M–R Reproduced with permission from ref [45]. Copyright 2024, American Chemical Society

Among various genes, the aggregation of soluble SNCA is a critical event in the neurodegenerative process of PD. Consequently, inhibiting the aggregation and fibrillation of SNCA has become a key therapeutic target for PD treatment. In this context, Guan et al. [43] developed a ZnO quantum dot-based nanoplatform (ZnO@Polymer-NpG), which consisted of glutathione (GSH)-modified, water-soluble ZnO nanoparticles (ZnO@Polymer) loaded with nerve growth factor (NGF) and plasmid DNA (pDNA) for PD treatment (Fig. 7H). The GSH modification endowed ZnO@Polymer-NpG with the ability to cross the blood–brain barrier (BBB). Specifically, GSH bound to the glutathione receptor (GSHR) on the BBB, facilitating receptor-mediated endocytosis and enabling transmembrane transport. Upon entering the acidic environment of the lysosomes, NGF and pDNA were released due to the reaction of pH-sensitive Zn–O bonds with hydrogen ions (H +) in ZnO@Polymer-NpG (Fig. 7I and G). The released pDNA contained genes capable of interfering with SNCA expression. These genes, through transcription, generated siRNA that silenced SNCA gene expression via a gene-silencing mechanism, ultimately leading to a reduction in α-syn synthesis (Fig. 7K). Concurrently, NGF facilitated the repair and protection of damaged neurons by promoting neuronal growth and enhancing neuronal function in PD models. After intravenous injection of ZnO@Polymer-NpG, prominent fluorescence was detected in the substantia nigra region of mice (Fig. 7L), confirming the brain-targeting delivery function of GSH. Notably, compared to other treatment groups, PD mice treated with ZnO@Polymer-NpG exhibited significant improvement in motor disorders. Additionally, the expression levels of SNCA and TH in the substantia nigra were markedly decreased. These findings suggest that ZnO@Polymer-NpG could effectively regulate PD by suppressing SNCA expression.

In recent years, CRISPR technology has emerged as a powerful tool in gene regulation, offering promising prospects for the treatment of PD. The dCas9 protein within the CRISPR system can be conjugated with various effector molecules, enabling diverse modes of gene expression regulation [44]. In the context of PD research, precisely modulating the expression of SNCA has become a focal point due to its direct association with the disease’s pathogenesis. Wang et al. [45] reported an epigenetic regulation system based on exosomal CRISPR intervention (RVG-CRISPRi-Exo), which consisted of exosome membranes encapsulating sgRNA targeting specific regions of the CpG island (CGI) in the murine SNCA gene, the dCas9-DNMT3A fusion protein, and RVG-Lamp2b, for PD treatment (Fig. 7M). RVG-CRISPRi-Exo crossed the BBB, as the RVG-Lamp2b moiety specifically bound to nicotinic acetylcholine receptors (nAChRs) on the surface of nerve cells, allowing for precise targeting of brain neurons (Fig. 7N). Once inside the cells, sgRNA and dCas9-DNMT3A, the core components of CRISPRi, worked to treat PD. The sgRNA acted as a guide, directing the dCas9-DNMT3A complex to specific CpG sites on SNCA, targeting the CGI in the murine SNCA gene. Upon reaching the CpG sites, dCas9 served as a scaffold protein, providing binding sites for DNMT3A. SNCA was methylated by DNMT3A, which possesses methyltransferase activity. This methylation altered the chromatin structure and impeded the binding of transcription factors to the gene promoter region, effectively inhibiting SNCA transcription and reducing α-syn expression (Fig. 7O). Consequently, neurotoxicity was alleviated, and motor behavior, balance, coordination, and neurosensitivity improved in PD model mice. After intravenous injection, RVG-CRISPRi-Exo accumulated in the brain within 1 h under focused ultrasound (FUS), with signal intensity gradually increasing over the next 6 h and declining slowly after 24 h (Fig. 7P). Behavioral assays revealed that PD mice treated with RVG-CRISPRi-Exo exhibited significant improvement in symptoms such as lethargy, motor disorders, and overall dullness compared to other treatment groups. Notably, α-syn expression was significantly suppressed in the substantia nigra pars compacta (SNpc) of PD mice after treatment with RVG-CRISPRi-Exo (Fig. 7Q). Additionally, synaptic function in striatal dopaminergic neurons was restored (Fig. 7R), and methylation levels at specific CpG sites were markedly elevated compared to other treatment groups. In conclusion, CRISPRi-Exo represents a promising therapeutic approach for PD, effectively inhibiting SNCA transcription through methylation of specific CpG sites, reducing α-syn expression, and showing potential for PD treatment.

Inhibition of α-syn aggregation via nanomaterials for PD treatment

The pathological aggregation of α-syn, a pivotal factor driving dopaminergic neurodegeneration in PD, results from its structural transition from soluble monomers to insoluble fibrils [46]. This aggregation initiates a cytotoxic cascade, characterized by increased intracellular ROS, mitochondrial dysfunction primarily through complex I inhibition, and the collapse of the mitochondrial membrane potential. These events ultimately lead to dopaminergic neuronal death and accelerate PD progression. Given its central role in neuronal toxicity, targeting α-synuclein aggregation is a critical therapeutic strategy for PD [47].

In recent years, the advent of nanotechnology in the medical domain has offered novel prospects for the treatment of PD. Zhang and colleagues [48] reported ROS-responsive nanoparticles (RPC NPs), composed of polydopamine (PDA) nanoparticles formed via oxidative polymerization as the structural backbone, loaded with curcumin (Cur) that inhibited and reversed α-Syn aggregation and scavenged ROS, and surface-modified with rabies virus glycoprotein (RVG) 29 peptide, for the treatment of PD (Fig. 8A). RPC NPs were capable of crossing the BBB and selectively targeting neuronal cells, a capability attributed to the RVG29 peptide’s high-affinity binding to neuronal nAChRs. After entering the cells, the abundant catechol and imine functional groups on the surface of PDA reacted with ROS, inducing structural changes in PDA and leading to the release of Cur (Fig. 8B). The released Cur bound to specific domains on α-Syn molecules, effectively preventing the aggregation of α-Syn monomers into fibrils and promoting the disassembly of pre-formed α-Syn fibrils (Fig. 8C), thereby impeding the pathological α-Syn aggregation. Furthermore, Cur contained antioxidant moieties such as phenolic hydroxyl groups, which reacted with excessive intracellular ROS (Fig. 8D), mitigating the oxidative damage to cells. After intravenous injection, RPC NPs exhibited intense fluorescence in the brain, indicating excellent brain-targeting capabilities (Fig. 8E). Behavioral assays demonstrated that treatment with RPC NPs significantly alleviated MPTP-induced motor deficits in mice, as evidenced by improved performance in the rotarod test, pole test, swimming test, and open-field test. Moreover, RPC NPs protected dopaminergic neurons in the substantia nigra of MPTP-treated mice, reduced α-Syn aggregation in the brain (Fig. 8F), and lowered ROS levels. Importantly, RPC NPs caused no histological damage to major organs in mice, highlighting their favorable biosafety profile and efficacy in PD treatment.

Fig. 8.

A Scheme of RPC NPs, B Fluorescence of α-Syn monomer and fibril growth, C TEM images of fibrils (right), D Scavenging efficiencies of HO, E Fluorescence imaging of mice, F WB of α-Syn and TH, G Scheme of NanoCA, H Cumulative drug releases from NanoCA, I TEM images of NanoCA at pH 7.4 and 5.0, J wb of n of LC3-II, TFEB, and LAMP1, K wb of TFEB and α-syn, L IVIS imaging of NanoCA@TPAAQ in mice, M CA in brain OB, CSF, plasma, and cerebrum. A–F Reproduced with permission from ref [48].

Copyright 2023, Elsevier. G–M Reproduced with permission from ref [50]. Copyright 2020, American Chemical Society

Aberrant aggregation of α‑syn in PD is tightly linked to dysfunction of cellular clearance pathways. Transcription factor EB (TFEB)—a master regulator of lysosomal biogenesis, autophagy, and lysosomal exocytosis—normally dephosphorylates and translocates to the nucleus to drive a coordinated CLEAR gene program [49]; in PD, however, TFEB becomes largely retained in the cytoplasm and colocalizes with Lewy pathology, compromising proteostasis. These observations, together with the limitations and adverse effects of mTOR‑dependent TFEB activation, motivate mTOR‑independent strategies. Liu et al. [50] developed a curcumin‑analogue nanoscavenger (NanoCA) by self‑assembling CA with COOH‑PEG‑COOH via reprecipitation to yield a PEG‑modified “pure‑drug” nanoformulation (Fig. 8G). After endocytosis, NanoCA undergoes pH‑responsive degradation in acidic endolysosomes (Fig. 8H and I), releasing CA that directly binds TFEB and promotes its nuclear translocation, thereby upregulating LC3‑II and lysosomal markers (LAMP1, CTSD), increasing autophagic flux, and enhancing α‑syn degradation (Fig. 8J and K); the effect on α‑syn is partially blocked by chloroquine, consistent with autophagy dependence. In parallel, NanoCA elevates intracellular Ca²⁺ levels and increases exosome secretion, with a higher α‑syn cargo in released exosomes. While prior work links TFEB to lysosomal exocytosis through Ca²⁺ signaling, the present study demonstrates the Ca²⁺ rise and exosome‑mediated α‑syn export under NanoCA treatment. For delivery, a rapid‑arousal intranasal delivery system (RA‑IDDS) was used to exploit a direct nose‑to‑brain route. Biodistribution studies showed preferential accumulation in the olfactory bulb and cerebrospinal fluid, with spread to striatum and substantia nigra, consistent with absorption along olfactory/trigeminal pathways and transit across the cribriform plate into CSF (Fig. 8L and M). This route bypasses, rather than “crosses,” the BBB in the classical sense. Functionally, intranasal NanoCA (5 mg/kg) ameliorated PD‑like behavioral deficits (forced swim, open field, DigiGait), preserved TH‑positive neurons/fibers in the nigrostriatal pathway, and reduced α‑syn monomers, oligomers, and higher‑order aggregates in midbrain tissue of MPTP‑intoxicated mice. NanoCA achieves dual clearance—TFEB‑mediated autophagic degradation and enhanced exosome secretion—via mTOR‑independent TFEB activation, offering a promising, noninvasive, and potentially translatable approach for PD.

Black phosphorus nanosheets (BPNSs) are an emerging two-dimensional nanomaterial composed of phosphorus atoms. They offer several remarkable advantages, such as excellent biosafety and high permeability through the BBB, which enables them to effectively deliver therapeutic agents to the brain. This characteristic is critical in treating neurological diseases like PD, where traditional drugs face challenges in crossing the BBB. BPNSs’ ability to penetrate the BBB facilitates their therapeutic effects directly at the sites of disease. Zhang et al. [51] reported on the neuroprotective effects of BPNSs in PD, specifically their ability to target and disrupt α-syn aggregates. The aggregation of α-syn is a hallmark of PD, contributing to neurotoxicity and neuronal death. Upon crossing the BBB, BPNSs bind to α-syn fibrils through hydrophobic interactions, reducing β-sheet content and destabilizing the fibrillar structures. This process leads to the dissociation of α-syn fibrils within 24 h. Moreover, BPNSs were found to restore autophagy pathways, which are typically impaired in PD due to α-syn aggregation. The increased autophagy activity enhances the degradation of α-syn aggregates, which further alleviates neuronal damage. BPNSs effectively reduced α-syn protein levels and the phosphorylated Ser129 form of α-syn, which is associated with the toxic aggregation state. Additionally, BPNSs elevated the expression of TH, a marker for dopaminergic neurons, and reduced the levels of active caspase-3, a marker of apoptosis, thereby preventing cell death and mitigating α-syn aggregation-induced damage. Upon intravenous administration in PD mouse models, BPNSs crossed the BBB and accumulated in the brain, where they were shown to improve motor behavior and prevent dopaminergic neuronal loss. Behavioral assessments indicated that BPNSs treated mice displayed improved motor performance in tasks such as the pole test, swimming test, and open-field test. Furthermore, histological and biochemical analyses confirmed that BPNSs treatment reduced α-syn aggregation and enhanced neuronal survival. These findings suggest that BPNSs are not only effective at reducing the aggregation of α-syn but also activate autophagic degradation pathways, protect neurons from mitochondrial dysfunction, and mitigate oxidative stress, which are key contributors to PD pathology.

Modulation of mitochondrial dysfunction with nanomaterials for PD treatment

Mitochondrial dysfunction is a core driver of PD, and selective mitophagy is essential for removing depolarized mitochondria and limiting the build-up of α-Syn [52]. Natural, biocompatible antioxidants have therefore drawn attention as modulators of mitophagy and neuronal redox balance.

Lycopene (LYC)—a carotenoid with strong singlet-oxygen scavenging activity—shows promise by enhancing mitophagy and protecting against MPTP-induced striatal dopamine loss in PD models. Yet clinical translation of LYC is constrained by low bioavailability and poor penetration of the BBB, which restrict its neuronal uptake and mitophagy-activating effect. To address these limits, Xia et al. [53] designed sequence-targeted LYC nanodots (TPP–rHuHF–LYC) (Fig. 9A). The construct uses recombinant human H-ferritin (rHuHF) nanocages to load LYC and decorates the outer surface with triphenylphosphonium (TPP). rHuHF engages transferrin receptor 1 (TfR1) on BBB endothelial cells to enable transcytosis, while the lipophilic TPP moiety directs the nanodots to neuronal mitochondria after entry into the brain. Once localized to mitochondria, encapsulated LYC quenches excessive ROS (Fig. 9B), restores redox homeostasis, and relieves oxidative suppression of mitophagy signaling. In PD models, this is accompanied by increased PINK1 and Parkin protein levels (Fig. 9C), a higher LC3-II/LC3-I ratio (Fig. 9D), and formation of autophagolysosomes, consistent with accelerated, selective removal of damaged mitochondria and preservation of mitochondrial homeostasis (Fig. 9E). In parallel, TPP–rHuHF–LYC modulates PD-related proteins by lowering Rab10, increasing TH, and clearing α-Syn aggregates (Fig. 9F and G). After intravenous dosing, fluorescently labeled TPP–rHuHF–LYC preferentially distributes to the substantia nigra and striatum within 1 h (Fig. 9H) and remains enriched for more than twelve hours, indicating effective delivery to PD-relevant regions. Short-course treatment (7 days) upregulates core components of the PINK1/Parkin pathway (PINK1, Parkin, Beclin-1), increases LAMP1, lowers p62, and shifts the autophagy-apoptosis axis toward survival (higher LC3-II/LC3-I, higher HO-1 and nuclear NRF2, lower cytoplasmic Keap1, and reduced cleaved caspase-3). Functionally, treated mice show improved motor behavior (shorter pole-test time, reduced tremor), recovery of dopamine and TH in the striatum, reduced α-Syn, and normalization of cholinergic readouts (ACh and AChE). These data support TPP–rHuHF–LYC as a neuron-targeted, mitochondria-addressed LYC platform that activates pro-survival mitophagy, stabilizes mitochondrial function, and mitigates PD-like pathology in preclinical models.

Fig. 9.

A Scheme of TPP-rHuHF-LYC Nanodots, B free radical scavenging of NPs, C expressions of mitophagy-related proteins (red: PINK1/Parkin; green: cytoskeleton; blue: nucleus), D Expression levels of mitophagy-related proteins; E TEM imaging of subcellular structures, F Immunofluorescent staining of the expressions of pathological proteins (red: PINK1/Parkin; green: cytoskeleton; blue: nucleus), G Expression levels of PD pathological proteins, H The fluorescently labeled nanodots in mice brain, I Scheme of RVG@AHM@Pt/CeO₂, J Characteristic protein expression, K TEM images of samples, L confocal laser scanning microscope (CLSM) images of mitochondria and Pt/CeO₂, M Fluorescent images of the head of PD mice, N TEM images of NR-RVG@AHM@Pt/CeO₂. A–H Reproduced with permission from ref [53].

Copyright 2023, American Chemical Society. I–N Reproduced with permission from ref [54]. Copyright 2023, American Chemical Society

While conventional antioxidants transiently neutralize extracellular/cytoplasmic ROS, they fail to address ROS overproduction from dysfunctional mitochondria—the root cause. Emerging nanotechnology, particularly single-atom catalysts with dual ROS-scavenging and mitophagy-inducing capabilities, offers a breakthrough. These nanomaterials not only eliminate existing ROS but also activate autophagy to clear ROS-generating damaged mitochondria, enabling sustained neuroprotection in PD. Zheng et al. [54] reported RVG29@AHM@Pt/CeO₂, composed of Pt/CeO₂ single-atom enzymes with a high density of surface oxygen vacancies and robust catalytic activity encapsulated within HL-60 cell membranes (AHM) modified with rabies virus glycoprotein (RVG29), for the treatment of PD (Fig. 9I). The AHM exhibited high-level expression of proteins including β2-integrin, LFA-1, and Mac-1, which could specifically interact with intercellular adhesion molecule-1 (ICAM-1) abundantly expressed on the surface of brain microvascular endothelial cells at inflammatory sites (Fig. 9J), and this interaction endowed RVG29@AHM@Pt/CeO₂ with the ability to target inflammatory regions and approach the BBB. Additionally, the neurotropic RVG29 bound to ACh receptors on the neuronal surface, and this binding event enabled RVG29@AHM@Pt/CeO₂ to traverse the BBB efficiently, facilitating its entry into the brain from the bloodstream and subsequent accumulation in the neuroinflammatory region. Once inside the cell, RVG29@AHM@Pt/CeO₂ preferentially localized around the mitochondria (Fig. 9K and L) because the positively charged Pt/CeO₂ electrostatically attracted and interacted with the mitochondria, which were negatively charged due to the mitochondrial membrane potential (Δψm). Pt/CeO₂, which exhibited catalase (CAT)-like, superoxide dismutase (SOD)-like, glutathione peroxidase (GPx)-like, and peroxidase (POD)-like activities, catalyzed the reaction between ROS and H⁺, depleting the H⁺ concentration surrounding the mitochondria and inhibiting the α-glycerophosphate shuttle pathway and the malate-aspartate shuttle pathway. As a consequence, the reduced form of nicotinamide adenine dinucleotide (NADH) in the cytoplasm was unable to supply an adequate amount of H⁺ to the mitochondrial matrix (MM) in a timely fashion, which disrupted and impaired the ability of mitochondrial respiratory chain complexes I, III, and IV to pump H⁺ from the MM into the mitochondrial intermembrane space (IMS), ultimately leading to the depolarization of Δψm. The depolarization of Δψm served as a critical signal that activated the expression of mitophagy-associated genes such as PINK1, Parkin, LC3B/LC3A, Atg5, FUNDC1, and P62, indicating that RVG29@AHM@Pt/CeO₂ effectively promoted mitophagy and thereby eliminated the root cause of ROS generation. Following tail-vein injection, distinct fluorescence signals of RVG29@AHM@Pt/CeO₂ were detected in the lesioned area (nigrostriatum) of the brains of PD model mice (Fig. 9M and N), demonstrating that RVG29@AHM@Pt/CeO₂ could penetrate the BBB in vivo, accumulate within the brain, and precisely target the lesioned sites. During the treatment process, PD model mice in the RVG29@AHM@Pt/CeO₂ treatment group exhibited significant improvements in movement disorders induced by PD in a series of behavioral tests, such as the rotarod test, pole test, adhesive test, open-field test, and forced-swimming test, underscoring the efficacy of the treatment. Post-treatment analysis revealed that the number of TH-positive cells in the substantia nigra striatum of mice in the RVG29@AHM@Pt/CeO₂ treatment group was substantially higher than that in the control group. Conversely, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) cells was significantly lower. These observations suggested that RVG@AHM@Pt/CeO₂ nanoparticles promoted mitophagy in dopaminergic neurons of the mouse striatum, eliminated the source of ROS production, increased the number of dopaminergic neurons in the striatum, and safeguarded neurons from damage.

Pu-Exos-PR is a plant-derived exosomal nanoplatform composed of Pueraria lobata–derived exosomes (Pu-Exos) that naturally encapsulate multiple bioactive macromolecules including a defined miRNA repertoire, and a ternary surface ligand DSPE-PEG-RVG (DPR) that endows the vesicles with pharmacokinetic and receptor-targeting advantages. Peng et al. [55] reported Pu-Exos-PR, composed of Pueraria lobata-derived exosomes encapsulating active components from Pueraria lobata and modified with the ternary ligand DSPE-PEG-RVG (DPR), for the treatment of PD. Exploiting exosomes’ non-lamellar, asymmetric lipid bilayers and 100–130 nm size, Pu-Exos-PR crosses nasal tissue and the BBB; RVG engages nAChRs enriched on brain microvascular endothelium, olfactory neurons, and dopaminergic neurons, while PEG increases hydrophilicity, prolongs circulation, and reduces mononuclear phagocyte clearance—together enhancing brain accumulation and cellular uptake. Once internalized, the Pu-Exos cargo recalibrates mitochondrial quality control by activating the PINK1–Parkin mitophagy axis and stabilizing the mitochondrial respiratory chain (MRC): TOMM7, PINK1, and SQSTM1/p62 are upregulated, LRRK2 is downregulated, Parkin expression is unchanged, and lysosome colocalization with perinuclear cargo release confirms effective processing—findings consistent with PINK1 accumulation on the outer mitochondrial membrane, Parkin recruitment, and p62-mediated autophagosome formation. In parallel, MRC performance is preserved, with increased complex I and V activities and elevated NDUFB4 and ATP5J2 expression, supporting ATP restoration and alleviating mitochondrial dysfunction. In PD mice, both intravenous and intranasal Pu-Exos-PR markedly improve motor and non-motor symptoms—including spontaneous activity, motor coordination, and depressive-like behavior—while reducing dopaminergic neuron degeneration, increasing Nissl body density, and enhancing TH expression, indicative of improved neuronal function. By coupling lipid-enabled barrier penetration and RVG-directed neuronal targeting with cargo-level modulation of mitophagy and respiratory-chain activity, Pu-Exos-PR offers a coherent, multi-node intervention that mitigates mitochondrial dysfunction and functional deficits in preclinical PD models while maintaining a favorable biosafety profile.

Modulating neuroinflammation with nanomaterials for PD therapy

Neuroinflammation is a central pathophysiological mechanism in PD. It involves the abnormal activation of microglia, astrocytes, and peripheral immune cells, leading to the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as excessive production of reactive oxygen and nitrogen species [56–58]. These inflammatory mediators accelerate dopaminergic neurodegeneration, impair synaptic plasticity, and disrupt neural circuit function. Chronic neuroinflammation also interacts with other pathological processes in PD, including α-synuclein aggregation, mitochondrial dysfunction, and dysregulated iron metabolism, thereby amplifying disease progression [59]. Consequently, strategies aimed at suppressing or modulating neuroinflammation have become a major focus in the development of disease-modifying therapies for PD.

Recent advances in nanotechnology have revolutionized drug delivery strategies, particularly in overcoming the BBB to deliver therapeutic agents to targeted neuropathological regions. Hu et al. [60] developed carrier-free nanocapsules (CRDA), synthesized from 4-formylphenylboronic acid (FBA) and dopamine (DA), and engineered with catalase (CAT) conjugated to cRGD (CAT-cRGD) and surface-modified with Angiopep-2 (Ang) for PD therapy (Fig. 10A). The cRGD moiety selectively binds to integrin receptors overexpressed on the PD-affected BBB, while Ang targets low-density lipoprotein receptor-related protein-1 (LRP-1) on the BBB, enhancing the nanocapsules’ ability to cross the barrier. This dual-targeting system synergistically improves CRDA adhesion to BBB endothelial cells, facilitating efficient penetration across the BBB and accumulation in the brain parenchyma (Fig. 10B). The stable boronate ester bonds between DA and FBA maintain drug encapsulation under physiological conditions (pH 7.4), ensuring stable systemic transport. In neuroinflammatory microenvironments, where pH is pathologically lowered (6.5–6.8), these bonds undergo pH-responsive hydrolysis (Fig. 10C), releasing both DA and CAT. The released CAT shows biphasic neuroprotective activity: initially scavenging ROS to restore redox balance (Fig. 10D), preventing DA oxidation and stabilizing neurotransmitter levels. This antioxidant effect also downregulates ROS-NFκB signaling, suppressing α-synuclein expression and activating ATF6 (Fig. 10E). Furthermore, the treatment mitigates endoplasmic reticulum stress and modulates microglial M1/M2 phenotype switching, resolving neuroinflammation. Following intravenous administration of CRDA, brain accumulation peaked at 5 h, with distribution across various regions including the hippocampus, midbrain, and cerebellum (Fig. 10F), demonstrating its superior brain-targeting ability. In PD mice, CRDA treatment significantly improved motor coordination, cognitive function, and exploratory behavior, confirming its efficacy in restoring learning, memory, and movement agility. Post-treatment analysis showed CRDA’s multi-target neuroprotective effects, significantly reducing α-syn (40.7%) and ATF6 (52.3%) levels in the striatum and substantia nigra, suggesting enhanced protein homeostasis. Moreover, CRDA reduced ROS by 2.8-fold and suppressed neuroinflammation, evidenced by 61% and 49% reductions in GFAP + astrocyte activation and Iba-1 + microglial proliferation, respectively (Fig. 10G). These combined actions on proteotoxic stress, oxidative damage, and glial-mediated inflammation validate CRDA’s therapeutic potential in slowing PD progression at molecular, cellular, and systemic levels.

Fig. 10.

A Schematic Illustration of HRDA, B Confocal microscopy images of NCs, C Release profiles of DA, D DCFH fluorescence, E Western blot images of TH and α-syn; F MRI scans showcasing the brain, G IHC staining for Iba-1, H Schematic illustration of MOF@Man Liposome nanozyme, I Immunofluorescence staining of NLRP3, Caspase-1, IL-6, and IL-1β, J Distribution of fluorescently labeled nanozyme systems, K Western blot assay of α-syn and TH expression, L Schematic Illustration of EVN, M WB analysis of the expression of Nrf2 and GPX4, N In vivo fluorescence imaging. A–G Reproduced with permission from ref [60].

Copyright 2024, Wiley‐VCH GmbH. H–K Reproduced with permission from ref [61]. Copyright 2023, Wiley‐VCH GmbH. L–N Reproduced with permission from ref [63]. Copyright 2024, American Chemical Society

Neuroinflammation is a central contributor to PD pathology, with aberrant activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in lesioned regions acting as a key driver of inflammatory cascades. To therapeutically intervene in this process, Fan et al. [61] developed a catalytic nanoplatform (MOF@Man Liposome) consisting of Zr–Fe porphyrinic MOF nanoparticles encapsulated within mannitol-modified liposomes composed of DSPE-PEG-Man, lecithin, and cholesterol (Fig. 10H). Mannitol decoration facilitated brain delivery through mannitol-mediated endothelial interactions and liposomal fusion, thereby enhancing transport across the blood–brain barrier. Once released into the parenchyma, the Zr–FeP MOF displayed dual enzyme-mimetic activities, decomposing H₂O₂ via catalase-like activity while concurrently scavenging superoxide radicals through superoxide dismutase (SOD)-like functionality. These complementary redox activities synergistically lowered intracellular ROS, thereby mitigating mitochondrial dysfunction and suppressing NLRP3 inflammasome assembly and activation (Fig. 10I). MOF@Man Liposome treatment attenuated neuroinflammatory responses, as reflected by reduced GFAP-positive astrocyte activation, diminished Iba-1-positive microglial proliferation, and decreased expression of inflammasome-associated proteins including NLRP3, caspase-1, and IL-1β in substantia nigra tissue (Fig. 10J). ELISA and cytokine profiling further confirmed downregulation of pro-inflammatory mediators such as IL-6, alongside upregulation of the anti-inflammatory cytokine IL-10, indicating a rebalanced neuroimmune milieu. Biodistribution studies using ICP-MS and ex vivo fluorescence imaging revealed significant accumulation of the nanoplatform in both the substantia nigra and striatum after intravenous injection (Fig. 10K). Behaviorally, treated animals exhibited marked improvements in motor performance and spatial learning compared with disease controls and non-targeted formulations.

The overactivated cerebral immune microenvironment is central to PD progression, driven by resident microglial neuroinflammation and sustained infiltration of peripheral inflammatory cells [62]. Wang et al. [63] designed an engineered extracellular vesicle–based nanoformulation (EVN) that integrates CCR2-enriched mesenchymal stem cell EVs as a shell with a ROS-responsive (Fig. 10L), diselenide-bridged mesoporous silica core loaded with dihydrotanshinone I (DT) (MSeN-DT). Along the CCR2–CCL2 chemotactic axis, the EV shell confers sequential brain targeting—supporting BBB transit in vitro and in vivo—and, crucially, acts as a nanodecoy to neutralize excess CCL2, thereby interrupting peripheral leukocyte recruitment to nigral lesions. MG1 peptides on the EV surface further refine cellular specificity toward M1-polarized microglia. In ROS-rich inflammatory niches, oxidative cleavage of diselenide linkages triggers on-demand DT release, which enhances Nrf2 nuclear accumulation and upregulates GPX4, diminishing oxidative stress and limiting microglial ferroptosis (Fig. 10M) while biasing microglia toward an anti-inflammatory M2 phenotype. In MPTP-induced PD mice, IVIS imaging showed brain accumulation peaking at 12 h (Fig. 10N), with subsequent colocalization in the SN microglial compartment; functionally, EVN improved locomotion and coordination (open-field, pole test) and restored spatial memory (Morris’s water maze). Consistent with immune rebalancing, striatum cytokine profiling revealed IL-10 and Arg-1 upregulation alongside TNF-α and IL-6 suppression, accompanied by reduced MPO (neutrophil infiltration marker) and fewer CD45 + CD11b + macrophages in brain tissue. Collectively, EVN couples’ chemokine-guided delivery and CCL2 sequestration with Nrf2–GPX4 pathway activation to recalibrate neuroinflammation and confer neuroprotection in PD models.

Modulating neuronal differentiation with nanomaterials for PD therapy

PD is characterized by progressive motor decline, which significantly limits patient quality of life and presents persistent challenges to conventional clinical interventions. Current therapeutic modalities, including dopaminergic pharmacotherapy and deep brain stimulation, provide symptomatic relief but are constrained by therapeutic ceilings and long-term adverse effects [64]. In this context, regenerative medicine has attracted increasing attention, with stem cell–based strategies offering the potential to replenish lost or dysfunctional neuronal populations. Among these, neural stem cells (NSCs) are particularly promising due to their inherent capacity to differentiate into both neuronal and glial lineages [65]. However, clinical translation remains hindered by obstacles such as inefficient neuronal conversion, uncontrolled lineage commitment, and limited functional integration. Achieving precise and efficient differentiation of NSCs into functional dopaminergic neurons is therefore a critical challenge. Emerging evidence suggests that nanomaterials, through their unique physicochemical properties and bioactive interfaces, can modulate stem cell behavior, providing novel opportunities to direct neurogenesis and enhance dopaminergic neuronal replacement in PD.

Retinoic acid (RA), an essential morphogen in neural development, suffers from poor aqueous solubility and rapid metabolic clearance, limiting its pharmacological utility. To overcome these barriers, Wang et al. [66] designed calcium–RA nanoparticles (Ca-RA NPs) through chelation-driven self-assembly of calcium acetate and RA for application in PD therapy. NSCs internalized Ca-RA NPs via a time-dependent endocytic pathway, with lysosomal localization detected at 3 h, progressive intracellular fluorescence intensification reaching a peak at 12 h, and subsequent decline at 24 h. This dynamic process reflected lysosomal sequestration and pH-responsive decomposition of the nanoparticles, resulting in controlled intracellular release of Ca²⁺ and RA. Functionally, nanoformulated RA markedly enhanced neuronal lineage commitment, as evidenced by elevated expression of βIII-tubulin (Tuj1) and MAP2, alongside dopaminergic specification markers including TH, dopamine transporter (DAT), and nuclear receptor-related 1 (Nurr1). In parallel, expression of gliogenic markers such as GFAP and Olig2 was suppressed, highlighting a shift away from astrocytic and oligodendrocytic differentiation. These molecular and phenotypic alterations were accompanied by a time-dependent increase in dopamine release, confirming the acquisition of a functional dopaminergic phenotype. Transcriptomic profiling and Gene Ontology enrichment analysis, further supported by pharmacological inhibition, revealed that the differentiation program induced by Ca-RA NPs was orchestrated through coordinated modulation of the MAPK and calcium signaling pathways. In vivo, stereotactic administration of Ca-RA NPs into the striatum of PD mice promoted preferential differentiation of NSCs into neurons, with increased TH-positive neuronal density and elevated dopaminergic marker expression after four weeks. Behavioral assessments demonstrated restored motor coordination in the rotarod test and improved cognitive performance in novel object recognition, compared with untreated controls. Collectively, these findings demonstrate that Ca-RA NPs can reprogram NSC fate toward functional dopaminergic neurons while limiting glial lineage progression, offering a nano-enabled strategy for regenerative intervention in neurodegenerative disorders.

Comparative synthesis and translational implications of nanomaterial-based strategies for PD

Collectively, nanomaterial-based strategies for PD can be broadly categorized into gene-regulatory platforms, aggregation-disrupting systems, mitochondria-targeted formulations, and immunomodulatory nanomedicines. Gene-regulatory systems such as siRNA-, plasmid-, and CRISPR-based carriers offer high mechanistic specificity toward SNCA, but their translational feasibility is constrained by delivery complexity, biosafety, and long-term genomic or epigenomic concerns. By contrast, aggregation-disrupting and ROS-scavenging platforms are generally easier to formulate and show broader neuroprotective effects, yet they may lack disease specificity and often rely on preclinical models that incompletely recapitulate progressive human PD. Mitochondria-targeted and inflammation-modulating nanoplatforms appear particularly promising because they intervene in convergent downstream pathways shared across PD phenotypes; however, uncertainties regarding long-term biodistribution, immunogenicity, batch reproducibility, and large-scale manufacturing still limit their clinical translation. Therefore, future studies should move beyond proof-of-concept efficacy and prioritize standardized safety evaluation, pharmacokinetic characterization, and validation in clinically relevant models.

Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is clinically characterized by progressive memory impairment, cognitive decline, and functional deterioration. Although currently available therapies can provide limited symptomatic benefit, they do not effectively stop the underlying neurodegenerative process [67]. From the perspective of nanotherapeutic development, the most actionable pathological mechanisms in AD include Aβ accumulation, tau hyperphosphorylation and propagation, neurotransmitter dysregulation [68], neuroinflammation, oxidative stress, and selected genetic risk pathways such as APOE- and TREM2-related dysfunction (Fig. 11 and Table 7). Rather than reviewing AD pathogenesis exhaustively, the following discussion highlights the mechanisms that are most directly relevant to nanomaterial-based intervention.

Fig. 11.

Molecular Mechanisms in AD Pathogenesis. Reproduced with permission from ref [69].

Copyright 2024. Published by Oxford University Press on behalf of Higher Education Press

Table 7.

Major mechanisms of AD pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
β-Amyloid hypothesis	Aberrant cleavage of APP by BACE1 and γ-secretase → generation of Aβ42 → oligomerization → plaque deposition	Synaptic dysfunction, calcium homeostasis disruption, mitochondrial impairment, neuronal death	BACE1 inhibitors, γ-secretase modulators, anti-Aβ oligomer antibodies, Aβ clearance enhancers
Tau hypothesis	Hyperphosphorylation of Tau → detachment from microtubules → NFT aggregation → trans-synaptic propagation	Microtubule destabilization, impaired axonal transport, neuronal dysfunction, cognitive decline	Kinase inhibitors (e.g., GSK-3β inhibitors), Tau aggregation inhibitors, Tau immunotherapy
Neurotransmitter abnormalities	Degeneration of cholinergic neurons → ACh deficiency; glutamate overrelease → NMDA receptor overactivation; 5-HT/dopamine dysregulation	Impaired memory and learning, excitotoxic neuronal injury, mood and behavioral disturbances	Acetylcholinesterase inhibitors (donepezil, rivastigmine), NMDA receptor antagonists (memantine), serotonergic/dopaminergic modulators
Neuroinflammation	Aβ-induced microglial activation (M2 → M1 phenotype shift) → IL-1β, TNF-α release; complement cascade activation (C1q, C3); astrocytic reactivity with loss of AQP4 polarity	Exacerbated neuroinflammation, aberrant synaptic pruning, impaired glymphatic clearance, accelerated Aβ accumulation	Microglial polarization regulators, complement inhibitors, anti-inflammatory cytokines, AQP4 polarity modulators
Oxidative stress	Mitochondrial complex I/IV dysfunction → ROS leakage; Aβ–Cu2 + /Fe2 + interaction → hydroxyl radical formation; Tau-induced impairment of mitochondrial transport	Lipid peroxidation (4-HNE), protein oxidation, DNA damage (8-OHdG), proteostasis disruption, apoptosis activation	Antioxidants (vitamin E, N-acetylcysteine), NOX inhibitors, metal chelators, mitochondrial function enhancers
Genetic factors	APP, PSEN1/2 mutations → familial early-onset AD; APOE ε4 allele → increased Aβ aggregation; TREM2, SORL1 risk variants → immune and endosomal–lysosomal dysfunction	Familial AD, enhanced amyloid deposition, microglial dysfunction, impaired endosomal trafficking	Gene editing/silencing therapies, APOE ε4 modulators, TREM2 activators, endosomal–lysosomal pathway regulators

(1) β-Amyloid Hypothesis

Aberrant cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase generates neurotoxic Aβ42 peptides [70]. Soluble Aβ oligomers, rather than mature plaques, are now recognized as the primary neurotoxic species, disrupting synaptic plasticity, calcium homeostasis, and mitochondrial function, and initiating glial activation that culminates in neuronal death [71].

(2) Tau Protein Hypothesis

Under physiological conditions, tau stabilizes microtubules, but hyperphosphorylation drives its detachment and aggregation into NFTs. This disrupts axonal transport, impairs intracellular trafficking, and promotes neuronal dysfunction [72]. Moreover, tau pathology propagates trans-synaptically, contributing to the stereotypical spread of neurodegeneration across brain networks.

(3) Neurotransmitter Abnormalities

Degeneration of basal forebrain cholinergic neurons reduces ACh, directly impairing learning and memory. Excessive NMDA receptor activation by glutamate induces excitotoxic Ca²⁺ influx, which can be partially ameliorated by NMDA antagonists such as memantine [73]. In parallel, serotonin (5-HT) and dopamine dysregulation contribute to neuropsychiatric symptoms including depression, anxiety, and, in later stages, psychosis.

(4) Neuroinflammation

Chronic activation of microglia by Aβ deposits drives a shift from protective (M2) to pro-inflammatory (M1) phenotypes, releasing cytokines such as IL-1β and TNF-α that exacerbate neuronal injury [74]. The complement cascade, particularly C1q and C3, mediates aberrant synaptic pruning. Astrocytic reactivity is also prominent; loss of aquaporin-4 (AQP4) polarity impairs glymphatic clearance, enhancing Aβ deposition and accelerating cognitive decline.

(5) Oxidative Stress

AD brains exhibit excessive ROS and RNS, arising from mitochondrial respiratory chain dysfunction, NADPH oxidase activation, and metal-catalyzed reactions involving Aβ–Cu²⁺/Fe²⁺ complexes [75]. ROS accumulation induces lipid peroxidation (elevated 4-HNE), protein oxidation, and DNA damage (8-OHdG), disrupting proteostasis and activating apoptotic cascades. Hyperphosphorylated tau further impairs mitochondrial trafficking, compounding oxidative injury.

(6) Genetic Factors

Autosomal dominant mutations in APP and PSEN1/2 underlie familial early-onset AD, whereas APOE ε4 strongly predisposes to late-onset disease by facilitating Aβ aggregation and tau pathology [76]. Recently, risk genes such as TREM2 and SORL1 have been implicated, linking immune dysregulation and endosomal–lysosomal dysfunction to AD pathogenesis [77, 78].

These mechanisms are highly interconnected: Aβ deposition can trigger neuroinflammation and oxidative stress, tau pathology contributes to synaptic and mitochondrial dysfunction, and genetic risk factors further influence immune and endosomal–lysosomal pathways. Because these biological nodes are directly targetable through controlled delivery, molecular modulation, and multifunctional nanoplatform design, they form the mechanistic basis of the AD-related nanotherapies discussed below.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-based modulation of Aβ pathology for AD therapy

AD is a debilitating neurodegenerative disorder, primarily marked by the extracellular accumulation of Aβ plaques in the brain. The abnormal aggregation and deposition of Aβ peptides are considered pivotal in the pathogenesis of AD, contributing to neuronal damage, synaptic dysfunction, and a progressive decline in cognitive abilities [79]. Despite substantial advances in research, conventional therapeutic strategies targeting Aβ have demonstrated limited success in clinical trials, underscoring the need for more effective treatment approaches. As the disease burden continues to rise globally, there is an urgent demand for innovative, disease-modifying therapies that can more efficiently target Aβ aggregation and its associated pathological consequences in AD.

Molecular chaperones are vital for maintaining cellular protein homeostasis. Heat shock proteins (HSPs), a key subclass of these chaperones, play an essential role in preventing protein misfolding and aggregation. HSPs recognize and bind to misfolded proteins through their hydrophobic domains, effectively preventing undesirable protein aggregation, while also assisting in transmembrane transport and proteolytic degradation [80]. In the context of AD, HSPs are crucial in regulating Aβ homeostasis, but their clinical translation remains challenging due to their intracellular localization, difficult extraction processes, high production costs, and challenges in targeted delivery to extracellular amyloid deposits. To address these limitations, Shi et al. [81] developed a novel mixed-shell polymeric micelle (MSPM) that mimics the functions of molecular chaperones for AD treatment (Fig. 12A). The MSPM is composed of poly(β-amino ester)-block-poly(ε-caprolactone) (PAE-b-PCL) and poly(ethylene oxide)-block-poly(ε-caprolactone) (PEG-b-PCL), which self-assemble into a nanostructure that mimics the hydrophobic recognition and sequestration mechanisms of natural chaperones. Under physiological conditions (pH 7.4), the PAE chains deprotonate, becoming hydrophobic and collapsing onto the micelle core. This configuration forms hydrophobic regions that bind to exposed hydrophobic residues on Aβ, effectively preventing its aggregation. Simultaneously, the hydrophilic PEG segments serve as a barrier, preventing the intermolecular aggregation of Aβ (Fig. 12B). Furthermore, MSPM reduces the binding of Aβ monomers and oligomers to cell membranes, thereby minimizing membrane damage and neuronal injury induced by Aβ (Fig. 12C). The nanochaperone-Aβ complex formed by the binding of Aβ to MSPM is readily engulfed by microglia, promoting Aβ clearance. This process reduces Aβ-induced inflammation and decreases the secretion of pro-inflammatory factors such as TNF-α and nitric oxide (NO), thereby maintaining normal microglial function and enhancing their phagocytic capacity. In vivo studies in APP/PS1 transgenic mice showed that MSPM treatment significantly reduced Aβ plaque expression in the cerebral cortex and hippocampus (Fig. 12D). Additionally, MSPM enhanced Aβ clearance by microglia (Fig. 12E), decreased the levels of TNF-α and cleaved caspase-3, and reduced neuronal apoptosis (Fig. 12F). Behavioral assessments revealed notable improvements in cognitive functions, including recognition memory and spatial orientation ability. MSPM nanochaperone effectively captures Aβ peptides, inhibits Aβ aggregation, promotes microglial phagocytosis of Aβ, alleviates Aβ burden, mitigates the inflammatory response, and ameliorates cognitive deficits in APP/PS1 transgenic mice.

Fig. 12.

A Schematic Illustration of MSPM, B TEM images of Aβ, C CLSM microscopy images of Aβ monomer, D Immunofluorescence images for Aβ expression, E Colocalization of Aβ (red) and IBA-1 (green) in the brain, F Western blot analysis, G Schematic Illustration of VP@RVG29, H TEM images of VP@RVG29 and VP@RVG29 in the presence of H₂O₂, I TEM images of nanoparticles on Aβ fibrillation, J Fluorescence images of Aβ, K Western blotting of SRA and LC3, L Bio-TEM images of microglia, M Ex vivo fluorescence imaging, N Schematic illustration of ERCD, O MSD curves of ERCD-1, P ThT fluorescence kinetic assay of Aβ40. A–F Reproduced with permission from ref [81].

Copyright 2019, WILEY‐VCH. G–M Reproduced with permission from ref [82]. Copyright 2023, Elsevier. N–P Reproduced with permission from ref [84]. Copyright 2024, Wiley‐VCH GmbH

Wang et al. [82] reported amyloid-targeting nanoparticle clusters (VP@RVG29) designed using a point-to-point matching strategy. These clusters are composed of VP nanoparticles (assembled from VCL, tBAm, PAm, and AAc), which serve as the core. The AAc groups are conjugated to 4-hydroxyphenylboronic acid (HPBA) through esterification and further modified with dopamine to anchor RVG29, aimed at treating AD (Fig. 12G). The functionalization of RVG29 enables VP@RVG29 nanoparticles to cross the BBB through interactions with ACh receptors. In the ROS-rich environment of AD, VP@RVG29 clusters (100 nm) disassemble into ultrasmall VP nanoparticles (7 nm) due to the ROS-responsive cleavage of boronate ester bonds in HPBA (Fig. 12H). The disassembly exposes additional Aβ-binding sites on the VP nanoparticles, which enhances their Aβ-binding affinity. This process disrupts Aβ-Aβ interactions and leads to the depolymerization of preformed Aβ fibrils into monomers (Figs. 12I). These monomers then reassemble with VP nanoparticles to form VP&Aβ complexes. The VP&Aβ complexes are efficiently internalized by microglia (Fig. 12J), leading to the upregulation of phagocytic receptors (SRA) and autophagy-related proteins (LC3) on the microglia (Fig. 12K), which enhances Aβ phagocytosis and degradation (Fig. 12L). Moreover, the VP&Aβ complexes mitigate neuroinflammation, reduce neuronal Aβ production, and exert neuroprotective effects, collectively improving AD pathology and alleviating memory deficits. Upon intravenous administration, VP@RVG29 exhibited strong fluorescence signals in the brain after 12 h, confirming its efficient brain-targeting capability (Figs. 12M). In therapeutic studies, VP@RVG29-treated APP/PS1 transgenic mice demonstrated significant improvements in memory, cognitive function, and spatial learning. Additionally, VP@RVG29 treatment significantly reduced Aβ plaque deposition in the brains of APP/PS1 mice. VP@RVG29 nanoparticle clusters, designed via the point-to-point matching strategy, represent a promising new approach to AD treatment.

Nanomotors, as advanced and intelligent nanoplatforms, have the ability to convert environmental energy into mechanical motion, presenting great promise in biomedical applications [83]. Among these, light-driven nanomotors are particularly advantageous due to their fuel-free operation, controllable movement, and biocompatibility. In this context, Sun et al. [84] reported a near-infrared (NIR)-driven multifunctional dual-carbon-dot nanomotor (ERCD), designed for AD therapy. The nanomotor consists of NIR-absorbing carbon dots (RCDs) with photooxidative and photothermal properties, coupled with epigallocatechin gallate-derived carbonized polymer dots (ECDs) that inhibit Aβ aggregation (Fig. 12N). The RCDs exhibit superior photothermal efficiency compared to the ECDs in ERCD-1 (ECD:RCD = 1:2.5), allowing NIR irradiation to preferentially heat the RCD region. This thermal gradient induces an osmotic pressure difference that propels the nanomotor toward the ECD domain (Fig. 12O). The ECD component of ERCD-1 directly suppresses Aβ aggregation, while the photodynamic and photothermal effects generated by the RCDs under NIR activation further amplify this inhibition (Fig. 12P). Upon NIR exposure, ERCD-1 generates ROS that oxidize amino acid residues on Aβ, altering its aggregation pathways. Simultaneously, the nanomotor’s movement enhances physical interactions with Aβ, leading to effective inhibition of Aβ40 and Aβ42 aggregation at ultralow concentrations (0.5 μg/mL), achieving inhibition rates of 92% and 73%, respectively. Moreover, the RCDs endow ERCD-1 with photooxidative activity under NIR, disrupting hydrogen bonds, electrostatic interactions, and hydrophobic forces within Aβ40 fibrils, destabilizing their structure. The combined effects of nanomotor propulsion and the intrinsic interactions between the carbon dots (CDs) and Aβ40 species facilitate the disruption of intermolecular salt bridges, breaking mature fibrils into smaller, amorphous aggregates. Fluorescence detection of ERCD-1-treated Caenorhabditis elegans (C. elegans) revealed its capacity to detect and disaggregate Aβ40 fibrils, acting as both a “scout” and “scavenger” for Aβ plaques. These findings demonstrate the potential of ERCD-1 as an effective therapeutic and diagnostic tool for AD.

Nanomaterial-mediated tau-targeted therapeutics for AD

Despite extensive research over several decades, Aβ-targeted therapies for AD have largely failed, with over 95% of clinical trials demonstrating insufficient efficacy [85]. Furthermore, the correlation between Aβ42 levels and cognitive decline remains weak (r ≈ 0.2), challenging the Aβ-centric paradigm. In contrast, tau pathology has emerged as a more promising target for therapeutic intervention, as its accumulation is more strongly correlated with disease progression (r ≈ 0.6–0.8). Under normal physiological conditions, tau stabilizes microtubules and facilitates axonal transport through dynamic binding. However, pathological hyperphosphorylation of tau causes a reduction in its affinity for microtubules (5–8 fold), leading to conformational changes, including the formation of β-sheet structures, and the assembly of neurotoxic paired helical filaments (PHFs) [86]. These events culminate in microtubule collapse, synaptic dysfunction, and neuronal death, processes that align with Braak stages of cognitive decline. Importantly, the spatiotemporal spread of tau pathology, which correlates more closely with symptom severity than amyloid deposition, underscores the potential of tau-targeted therapeutics as a transformative approach for AD treatment.

However, current therapeutic strategies targeting tau also face significant translational challenges, as exemplified by the limited clinical efficacy of tau-targeting agents like Tideglusib, despite their ability to inhibit pathological tau aggregation [87]. This challenge has driven growing interest in alternative strategies, including the use of natural polyphenolic antioxidants, such as tannic acid (TA), which exhibit dual therapeutic mechanisms: scavenging neurotoxic ROS and suppressing tau aggregation through specific recognition of the R3 domain [88]. Nevertheless, the clinical application of TA is hindered by rapid metabolic clearance and structural instability, highlighting the critical need for nanotechnology-enabled delivery platforms to enhance pharmacokinetics and improve target engagement. In response to these challenges, Yang et al. [89] developed multifunctional neuron-targeted nanocomposites, IR780-Mn@TA-TPL NPs, for AD therapy (Fig. 13A). These nanoparticles integrate IR780 (NIR fluorescent dye), Mn²⁺ (for magnetic resonance imaging), polyphenolic antioxidant TA, and the TPL peptide (which facilitates neuron targeting). The TPL peptide, synthesized by fusing the BBB-penetrating peptide TGN with the neuron-binding peptide Tet1 via a tetraglycine linker, enables efficient BBB crossing (Fig. 13B). Upon entering diseased cells, TA within the nanocomposite recognizes and binds to the R3 peptide domain of tau, forming hydrogen-bonded hairpin structures (Fig. 13C), which prevent pathological tau conformational changes. This interaction activates the Akt/GSK-3β signaling pathway, reducing tau hyperphosphorylation and decreasing the expression of phosphorylated tau (p-tau) and neurotoxic tau fibril aggregation (Figs. 13D and E). Additionally, TA reduces intracellular ROS levels and restores mitochondrial membrane potential. It also inhibits neuronal apoptosis by downregulating pro-apoptotic proteins, such as Bax and caspase-3 (Fig. 13F). Upon stereotactic brain injection, IR780-Mn@TA-TPL NPs exhibited the strongest fluorescence signals in the hippocampus of rat brains, demonstrating superior neuronal targeting capability (Figs. 13G and H). In AD rat models treated with these nanoparticles, significant improvements in learning and memory functions were observed, with notable reductions in mitochondrial ROS levels and p-tau expression.

Fig. 13.

A Schematic illustration of IR780-Mn@TA-TPL NPs, B Confocal microscopic images, C TEM images of tau protein aggregation, D Western blot images for p-tau and total tau protein expression, E Representative fluorescence images, F western blot images of Bax, c-Caspase3, p-Akt (p-Ser473), total AKT, p-GSK3β (p-Ser9), G IVIS images of rats, H In vivo T1-weighted MR images of the brain, I Schematic Illustration of BVNC, J CLSM images, K TEM images of tau fibrils, L TEM of tau, M CLSM images of PBS, VNC, BNC, and BVNC to inhibit tau aggregation, N Bio-TEM images of autophagosomes, O Western blot analysis of autophagic-related protein, P Bio-TEM images of autophagic vesicles in mice brain. A–H Reproduced with permission from ref [89].

Copyright 2024, Ivyspring International Publisher. I–P Reproduced with permission from ref [92]. Copyright 2024, Wiley‐VCH GmbH

Enhancing the cellular clearance of pathogenic tau protein is a major focus in AD research. However, current strategies aimed at improving tau clearance face significant challenges. For instance, proteasome activators are ineffective in degrading pre-existing tau aggregates, while impaired autophagy in AD brains—characterized by tau-induced microtubule depolymerization and disrupted autophagosome-lysosome fusion—limits the removal of abnormal proteins [90]. Existing small-molecule autophagy modulators show limited efficacy due to their inability to restore autophagic pathways and their nonspecific targeting. Although chaperone-mediated autophagy (CMA), a selective degradation mechanism, holds therapeutic potential, its dysfunction in neurodegenerative diseases—driven by the conformational changes in pathogenic proteins—further complicates the development of viable treatments [91]. These limitations highlight the need for innovative approaches that can simultaneously address tau aggregation and restore autophagic-lysosomal flux with high spatial precision. In this regard, Shi et al. [92] reported the development of Beclin1-VQIINK-nChap (BVNC) as a novel therapeutic approach for AD, designed to facilitate selective tau clearance. The BVNC system is composed of a hydrophobic microdomain formed by surface-modified polyethylene glycol-b-polycaprolactone (PEG-b-PCL) and poly(β-amino ester)-b-polycaprolactone (PAE-b-PCL), along with the tau-targeting peptide VQIINK and the autophagy-activating peptide Beclin1. Under physiological conditions (pH 7.4), the PAE chains undergo a spontaneous phase transition from hydrophilic to hydrophobic, forming chaperone-like hydrophobic microdomains (Fig. 13I). Once introduced into the body (Fig. 13J), the VQIINK peptide specifically recognizes and binds to pathological tau proteins and their aggregates (Fig. 13K). The hydrophobic microdomains in the BVNC system then interact with tau, helping maintain tau homeostasis and microtubule stability (Figs. 13L and M). Simultaneously, Beclin1 peptides activate autophagy in situ (Fig. 13N), as evidenced by the increased expression of autophagy-related proteins such as LC3B, ATG5, and LAMP1, and the reduced expression of the autophagy receptor p62 (Fig. 13O). This activation promotes the sequestration of tau aggregates in autophagosomes, which are then transported along stabilized microtubules for fusion with lysosomes, enhancing autophagic flux and facilitating the degradation of pathogenic tau. BVNC treatment significantly reduced tau burden and neuronal damage in AD brains. In stereotactically injected PS19 mice, BVNC-treated mice demonstrated improved hippocampal-dependent memory, nesting behavior, and learning compared to controls (Fig. 13P). The BVNC group exhibited the highest expression of LC3B in the hippocampus, accompanied by reduced tau deposits and apoptotic markers, demonstrating its dual efficacy in tau clearance and neuroprotection through coordinated autophagy activation.

Autophagy dysregulation is closely associated with the accumulation of pathogenic tau proteins during the progression of AD, positioning the modulation of autophagy via nanomaterials as a promising therapeutic strategy [93]. The incorporation of homing proteins can enhance the specificity of nanomaterials, guiding them to target diseased cells or tissues, thereby improving treatment precision. Ling et al. [94] reported a tau-targeted homing nanoassembly (THN) for AD treatment, composed of autophagy-inducing ceria nanoparticles (CNPs), a tau-recognizing anti-tau antibody (AT8), and carrier magnetic mesoporous silica nanoparticles (M-MSNs). The AT8 antibody specifically binds to the phosphorylated sites (Ser202/Thr205) of pathogenic tau, enabling the THN to selectively accumulate in tauopathy-associated cells and bind to hyperphosphorylated tau and its aggregates. The CNPs within the THN assembly activate autophagic flux by enhancing lysosomal function and promoting autophagosome formation, as evidenced by elevated LC3-I/LC3-II expression, facilitating the degradation of pathogenic tau and suppression of neuroinflammation. Additionally, the CNPs exhibit CAT-like activity, scavenging reactive oxygen species (ROS) while inhibiting the AKT/mTOR signaling pathway, which further supports tau degradation. Following stereotactic injection in AD rats, MRI confirmed THN accumulation in the hippocampus, demonstrating its effective in vivo targeting. PET imaging revealed a reduced tau burden and inhibited microglial activation in the THN-treated group. Behavioral assessments showed significant improvements in learning and memory, further validating the therapeutic impact of THN. Collectively, THN represents a multi-faceted therapeutic approach, achieving selective tau aggregation targeting, autophagy-mediated degradation via lysosomal reactivation, and ROS scavenging-driven neuroprotection. This nanoplatform establishes a novel paradigm for precision AD intervention by coupling the recognition of pathological biomarkers with multimodal therapeutic modulation.

Nanomaterial-mediated restoration of redox homeostasis for AD therapy

Oxidative stress and neuroinflammation are pathologically interconnected in AD, with both mechanisms contributing to the progression of neuronal damage. This has spurred significant efforts to develop safer anti-inflammatory therapies that also restore redox homeostasis. While conventional anti-inflammatory drugs have shown partial efficacy in alleviating AD symptoms, their systemic toxicity remains a major concern. This highlights the urgent need for targeted therapies that can effectively mitigate neuroinflammation and oxidative stress while minimizing off-target effects. Nanomaterial-based strategies have emerged as a promising approach for addressing these challenges, offering the potential for more precise modulation of redox balance and inflammation in AD therapy.

Molecular hydrogen (H₂) has emerged as a promising therapeutic candidate for AD due to its dual antioxidant properties: selective scavenging of highly cytotoxic ROS, such as hydroxyl radicals (•OH), and its exceptional biosafety profile. H₂ is capable of rapid diffusion across biological barriers, offering significant potential for treating oxidative stress in neurodegenerative diseases [95]. However, clinical translation of H₂ therapy is limited by its low aqueous solubility (1.6 ppm), which restricts its sustained therapeutic accumulation at lesion sites. Recent advancements in nanomaterial engineering have addressed this challenge by developing palladium (Pd)-based platforms, which leverage Pd’s unique crystalline hydrogen storage capacity (up to 900 × volume absorption) and its nanoscale-enhanced catalytic activity to facilitate controlled H₂ release. This synergy between gas therapy and nanotechnology offers new possibilities for precision AD intervention by achieving spatiotemporal modulation of oxidative stress pathways. He et al. [96] reported the development of small-sized Pd hydride (PdH) nanoparticles, composed of Pd and hydrogen, for AD therapy (Fig. 14A). Upon reaching damaged brain regions, Pd facilitated the release of hydrogen atoms from the PdH nanoparticles through self-catalytic effects (Fig. 14B). The released hydrogen existed in a bioreductive state, selectively neutralizing cytotoxic •OH (Fig. 14C), thereby alleviating oxidative stress-induced neuronal damage. This system also enhanced mitochondrial energy metabolism by upregulating cytochrome c oxidase subunit IV (COX IV) expression, while suppressing β-secretase 1 (BACE1) and amyloid precursor protein (APP) overexpression, ultimately reducing Aβ production and aggregation. Concurrently, PdH nanoparticles activated intracellular antioxidant defenses through heme oxygenase-1 (HO-1) induction and the Nrf2-antioxidant response element (ARE) pathway. Following stereotactic brain administration, PdH-treated AD mice showed significant improvements in spatial learning, memory, and depression/anxiety-related behaviors compared to other treatment groups. Additionally, •OH levels in the hippocampi of PdH-treated AD mice were markedly reduced, accompanied by lower expression of APP and BACE1 (Fig. 14D), further inhibiting Aβ generation (Fig. 14E). Notably, PdH treatment restored mitochondrial function, activated the Nrf2-ARE pathway (Fig. 14F), increased the expression of synaptic proteins (PSD95, Syn1, and SYN) in the hippocampus (Fig. 14G), and promoted synaptic functional recovery, neuronal damage reversal, and increased density of Nissl bodies.

Fig. 14.

A Schematic illustration of PdH nanoparticle, B Sustained hydrogen release profile of PdH nanoparticle, C concentrations of ROS and ∙OH, D The levels of APP, BACE1 and sAPPβ, E Immunoblotting pattern of the expressions of Aβ, F The expressions of Nrf2 and HO-1 in mice hippocampus, G Immunoblotting of synaptic proteins, H Schematic illustration of K-CAC, I Transport efficiency of nanoparticles across the BBB, J Confocal microscope of the ROS probe DCFH-DA, K TEM images of Aβ monomers, L head images of mice, M Temperature rise profile, N photothermal images of the brain. A–G Reproduced with permission from ref [96].

Copyright 2019, Elsevier. H–N Reproduced with permission from ref [100]. Copyright 2022, American Chemical Society

In AD, extracellular Aβ plaques exhibit abnormally high concentrations of Zn²⁺, reaching up to 1 mM, which provides a unique clue for developing novel therapeutic strategies. The aggregation of Zn²⁺ at elevated concentrations is closely associated with Aβ deposition and aggregation, and it is intrinsically linked to the exacerbation of oxidative stress [97]. Elevated Zn²⁺ levels may disrupt redox reactions, promoting the production of ROS and exacerbating oxidative damage to neurons. Liu et al. [98] reported a novel Zn²⁺-responsive nanomedicine platform (NWP) for AD treatment, which incorporates palladium nanoclusters (Pd NCs) as carriers, loaded with nerve growth factor (NGF) and encapsulated by a supramolecular nanovalve containing carboxylated pillar[5]arene (WP5). Pd NCs, exhibiting antioxidase-like activity, effectively reduce intracellular ROS production in damaged cells, thus mitigating oxidative stress-induced neuronal injury. NGF provides neuroprotection by promoting the growth and survival of impaired neurons, as well as enhancing their resistance to oxidative stress. The WP5 supramolecular nanovalve is activated by elevated Zn²⁺ concentrations in lesion areas through Zn²⁺ chelation, triggering the controlled release of NGF to further enhance cellular antioxidant capacity. This coordinated mechanism protects neurons from oxidative damage, alleviates AD-related pathologies (e.g., reduced Aβ deposition, modulation of microglial polarization, and suppression of inflammatory cytokine release), and improves learning and memory performance in AD model mice.

Among various nanomaterials, cerium dioxide (CeO₂) nanoparticles are recognized for their unique redox enzyme-like activity, resulting from their mixed valence states of Ce³⁺ and Ce⁴⁺ on the surface [99]. This activity enables CeO₂ to scavenge ROS, providing antioxidant protection and demonstrating significant potential for applications such as photocatalysis, especially as n-type semiconductor materials. Gold nanorods (Au NRs), with their tunable optical and electrical properties, further complement this strategy through their photothermal effects under NIR light. Building upon these properties, Wang et al. [100] developed a novel nanocomposite, KLVFF@Au-CeO₂ (K-CAC), composed of Au NRs and CeO₂ nanoparticles, with CeO₂ selectively grown at both ends of the Au NRs. The central region of this composite was modified with the Aβ-targeting inhibitory peptide KLVFF, intended for AD therapy (Fig. 14H). The KLVFF peptide endows the K-CAC nanocomposite with the ability to penetrate the BBB and specifically target disease cells. The photothermal effect of the Au NRs significantly enhances the ability of the composite to traverse the BBB under NIR irradiation (Fig. 14I). CeO₂ nanoparticles, acting as enzyme mimetics, utilize their Ce⁴⁺/Ce³⁺ redox cycling capacity to scavenge excess ROS within AD-affected cells (Fig. 14J). Under NIR irradiation, the Au NRs produce hot electrons, which are injected into the conduction band (CB) of CeO₂, amplifying its catalytic ROS decomposition efficiency by 2.3-fold. Simultaneously, the photothermal properties of the Au NRs enable the targeted ablation of Aβ aggregates in AD (Fig. 14K). Upon intravenous injection and NIR irradiation at 808 nm, K-CAC accumulation in the brains of APP/PS1 mice peaked at 8 h (Fig. 14L), with the head temperature rising to 40.6℃ within 10 min (Fig. 14M). Notably, K-CAC-treated mice exhibited significant improvements in learning, spatial memory, and cognitive function. Furthermore, Aβ plaque burden was significantly reduced, and neuronal loss was inhibited in the brains of K-CAC-treated APP/PS1 mice (Fig. 14N).

Nanoparticle-mediated gene expression modulation for AD therapy

In the pathological progression of AD, the abnormal metabolism and deposition of Aβ are central to disease development. Aβ is generated through the sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The overexpression of APP and BACE1 leads to the excessive production and aggregation of Aβ, which in turn triggers neuronal damage, inflammatory responses, and cognitive decline. Therefore, modulating the expression of these genes represents a crucial therapeutic target for intervening in the pathogenesis of AD. Recent advancements in nanoparticle-mediated gene expression modulation have shown promise as a strategy to selectively regulate the expression of APP and BACE1, offering a novel approach to reducing Aβ production and mitigating its toxic effects.

MicroRNA-124 (miR-124) is abundantly expressed in healthy brains but significantly reduced in AD patients. It binds to the 3’ untranslated region (3’UTR) of target mRNAs, post-transcriptionally regulating the expression of multiple AD-related genes [101]. Notably, miR-124 shows strong potential in suppressing the expression of BACE1 and APP, making it an ideal candidate for AD gene therapy. However, its clinical application is hindered by rapid degradation in vivo, short half-life, poor cellular membrane permeability, and inefficient BBB penetration. To overcome these limitations, Tong et al. [102] developed a DNA nanoflower (DF)-based delivery system, Rutin@DF-miR-124/RVG29 (RDMR), for AD treatment (Fig. 15A). This system comprises DNA nanoflowers (DFs) as carriers, a miR-124 chimera, RVG29 peptide, and Rutin. The RVG29 peptide facilitates BBB penetration by specifically binding to α7 nAChR on endothelial and neuronal membranes, promoting transcytosis across the BBB (Fig. 15B). Upon entering the acidic microenvironment of AD-affected regions, the DFs undergo structural changes that partially unwind their double-stranded DNA, triggered by acidic conditions. This process releases the miR-124 chimera and Rutin. The released miR-124 chimera enters neurons and binds to the 3’UTR of target mRNAs, post-transcriptionally regulating gene expression to suppress AD-related genes such as BACE1 and APP (Fig. 15C). This effectively reduces Aβ production (Fig. 15D), improves synaptic plasticity, inhibits neuroinflammation, and modulates tau phosphorylation, thereby addressing key aspects of AD pathology at the genetic level. Rutin, a small molecular drug, synergizes with miR-124 through its anti-inflammatory, antioxidant, and Aβ-inhibitory activities, further suppressing Aβ generation and alleviating neuroinflammation. Together, these components target multiple AD-related pathological pathways, achieving combinatorial gene therapy. Following tail vein injection, fluorescence signals of RDMR were detected in the brain at 1 h, peaking at 12 h (Fig. 15E), demonstrating its strong brain-targeting capability. After a 30-day treatment, APP/PS1 mice exhibited significantly increased miR-124 expression, suppressed BACE1 levels in the hippocampus, reduced Aβ plaque burden (Figs. 15F and G), and decreased inflammatory cytokines (IL-6, IL-1β, and TNF-α).

Fig. 15.

A Schematic illustration of RDMR, B Representative fluorescence images, C BACE1 expression, D Protein expression of APP and Aβ, E Representative in vivo fluorescence images, F An amplified image of Aβ plaque in the hippocampal region, G Representative image of Aβ staining in the hippocampal region, H Schematic illustration of TR-ZC/RNAi/AAP, I CD22 expression, J Colocalization of FITC-Aβ1 − 42 and lysosomes, K IL-1β, TNF-α, and IL-6 expression, L In vivo imaging. A–G Reproduced with permission from ref [102].

Copyright 2022 Wiley–VCH GmbH. H–L Reproduced with permission from ref [104]. Copyright 2023, Wiley–VCH GmbH

Dysfunctional microglia play a pivotal role in the pathological progression of AD. Studies have shown that CD22 is abnormally overexpressed in aged microglia, which is closely associated with reduced phagocytic clearance of Aβ, increased release of inflammatory cytokines, and activation of the complement system [103]. These effects contribute to excessive Aβ accumulation in the brain, neuronal damage, and ultimately cognitive decline. Therefore, modulating CD22 expression through gene therapy offers a promising strategy for restoring microglial function and represents an important research direction for AD treatment. However, conventional gene therapy vectors, such as viral and non-viral carriers, are hindered by limitations such as immunogenicity, carcinogenicity, high cost, and functional simplicity, which restrict their clinical applicability. To address these challenges, the development of novel, efficient, and safe gene delivery systems is urgently needed. In this regard, Nie et al. [104] reported a transferrin receptor (TfR) aptamer-functionalized, erythrocyte membrane-camouflaged nanomedicine delivery system (TR-ZRA) for AD treatment. This system is composed of a Zn-CA metal–organic framework (ZC), CD22 shRNA plasmid (RNAi), Aβ aptamer (AAP), and TfR aptamer-modified erythrocyte membrane (TR) (Fig. 15H). The TR-ZRA system utilizes TfR aptamers on its surface to bind TfR on brain endothelial cells, facilitating efficient BBB penetration and cellular uptake. Upon intracellular entry, the CD22 shRNA suppresses CD22 gene overexpression in aged microglia via RNA interference (Fig. 15I), thereby restoring the microglial phagocytic capacity for Aβ clearance (Fig. 15J). This enhanced microglial phagocytosis of Aβ reduces pathological Aβ accumulation and inhibits complement activation through the chlorogenic acid present in Zn-CA. This leads to a decrease in complement component levels, alleviating neuronal damage and neuroinflammation (Fig. 15K). Additionally, the Aβ aptamer (AAP) specifically binds to Aβ plaques, enabling fluorescence-based monitoring of Aβ burden in vitro, which aids both disease evaluation and therapeutic assessment. Following tail vein injection, TR-ZRA exhibited strong fluorescence signals in the brains of APP/PS1 mice at 72 h, with fluorescence intensities 2.0-fold and 1.24-fold higher than those in the ZC and ZRA groups, respectively (Fig. 15L), demonstrating superior brain targeting and BBB penetration. After 30 days of treatment, CD22 mRNA and protein expression in mouse brain tissues were significantly suppressed, accompanied by reduced hippocampal inflammation and Aβ deposition. Furthermore, TR-ZRA-treated APP/PS1 mice showed significant improvement in memory deficits.

BACE1 is a key enzyme in the production of Aβ, and its inhibition is a crucial strategy to reduce Aβ accumulation. Similarly, TREM2 plays a critical role in regulating microglial function, and modulating its expression is vital for AD therapy. However, one of the primary challenges in gene therapy for AD is achieving effective BBB penetration. Nanotechnology offers innovative solutions, particularly through the use of biomimetic nanomaterials, which demonstrate significant advantages for targeted drug delivery. Wang and colleagues [105] reported a ROS-responsive biomimetic exosome-liposome hybrid nanovesicle (TSEL) for AD treatment, comprising exosomes, liposomes, and angiopep-2 (Ang2) peptides conjugated to the liposomes. The homing capabilities of both exosomes and Ang2 peptides synergistically enabled BBB penetration. Specifically, Ang2 interacts with LRP1 receptors expressed on neurons and the BBB, facilitating targeted delivery. Upon reaching the brain, TSEL responds to the high ROS microenvironment in AD lesions. The ROS-sensitive “Se-Se” bond in DSPE-Se-Se-PEG-Ang2 undergoes cleavage, triggering TSEL disassembly and the controlled release of siBACE1 and pTREM2. The released siRNA enters the nucleus and downregulates BACE1 gene expression, reducing Aβ production at its source, thereby alleviating neuronal damage and suppressing pro-inflammatory responses in the AD brain. Simultaneously, the released pTREM2 enhances TREM2 expression, which promotes the polarization of microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. This shift enhances microglial phagocytic clearance of Aβ plaques, curtails neuroinflammation, and protects neurons from damage, ultimately contributing to therapeutic effects against AD. Following tail vein injection, fluorescence signals from TSEL were detectable at 1 h and peaked at 24 h, indicating efficient brain targeting. Post-treatment analysis of the hippocampus and cortex in AD mice revealed that the TSEL-treated group showed significantly increased APP and TREM2 protein expression and reduced BACE1 levels compared to other groups. Furthermore, pro-inflammatory cytokines (IFN-γ, IL-6) were downregulated, while the anti-inflammatory cytokine IL-10 was upregulated in TSEL-treated mice. Behavioral assessments demonstrated that TSEL-treated APP/PS1 mice exhibited marked improvements in spatial cognition and memory performance compared to other treatment groups.

Nanoparticle-mediated NSC reprogramming for AD therapy

Neural stem cell (NSC) regenerative therapy holds considerable promise for AD treatment by generating functional neurons capable of integrating into existing synaptic networks to repair damaged neural circuits. However, the practical application of NSC therapy faces several significant challenges. For example, the hostile microenvironment of AD brains adversely impacts the survival and proliferation of transplanted NSCs, limiting their short-term efficacy [106]. While NSCs can promote synaptic connectivity, their limited capacity to clear Aβ and tau aggregates impedes their ability to effectively mitigate the pathological changes caused by these accumulations. Moreover, the AD pathological environment, particularly the high concentrations of toxic Aβ oligomers, inhibits NSC differentiation into neurons, thus reducing neuroregeneration in the brain. To address these limitations, Wang et al. [107] developed a high-efficiency gene and drug delivery nanosystem, PBAE-PLGA-Ag₂S-RA-siSOX9 (PPAR-siSOX9), for AD therapy (Fig. 16A). The system consists of poly(β-amino ester) (PBAE), poly(lactic-co-glycolic acid) (PLGA), silver sulfide quantum dots (Ag₂S QDs), RA, and a SOX9 siRNA (siSOX9)-expressing plasmid. The PBAE-PLGA nanocarrier successfully delivered RA and siSOX9 to NSCs (Fig. 16B), where RA activated RAR-dependent transcription to promote the production of NeuroD1 and β-catenin. At the same time, the siSOX9 plasmid downregulated SOX9 levels, relieving its inhibitory effect on the Wnt/β-catenin signaling pathway (Fig. 16C). This dual modulation synergistically enhanced both Wnt/β-catenin and RA signaling, thereby driving NSC differentiation toward neurons. These differentiated neurons contribute to repairing damaged neural networks and improving neurological function in AD mouse models. Additionally, genetically engineered NSCs expressing neprilysin (NEP) continuously degrade Aβ through membrane-bound NEP and NEP-enriched extracellular vesicles (EVs) (Fig. 16D). This process alleviates Aβ toxicity, improves NSC survival in the AD microenvironment, and promotes neuronal regeneration and neural circuit repair. Furthermore, the Ag₂S QDs in the system enabled real-time monitoring of nanomaterial distribution and cell transplantation in vivo. NEP-NSCs were transplanted into the hippocampus of AD mice via stereotactic injection (Fig. 16E). After 6 months of treatment, AD mice showed significantly reduced Aβ deposition, with some transplanted NEP-NSCs differentiating into Tuj1-positive neurons (Fig. 16F), thereby enhancing neuroregeneration. NEP-NSC-treated AD mice exhibited significant improvements in cognitive and memory functions.

Fig. 16.

A Schematic of PPAR-siSOX9, B Fluorescence microscopy image, C Expression of Wnt2b, NeuroD1, GSK3β, SOX9, and β-catenin, D Expression of NEP, E In vivo NIR-II imaging, F Quantification of Tuj1, G Schematic of CaFO, H Fluorescence images; I TEM images of NSCs, J UV–vis spectra of CaFO nanoparticles, K Western Blot of ChAT expression, L The intracellular Ach content, M Fluorescence images of representative brain tissue sections, N Q-PCR results of the mRNA levels of ChAT and Map2. A–F Reproduced with permission from ref [107].

Copyright 2021 Wiley–VCH GmbH. G–N Reproduced with permission from ref [109]. Copyright 2022, American Chemical Society

Currently, AD treatment faces significant challenges, particularly in the restoration or repair of damaged cholinergic neurons. This gap underscores the urgent need for effective therapeutic strategies. NSC therapy offers new hope, as NSCs can differentiate into functional neurons and glial cells. However, a major limitation of this approach is the inability of transplanted NSCs to specifically differentiate into cholinergic neurons, which are critical for restoring cognitive functions in AD patients. In recent years, the role of metal ions in neurodegenerative disease treatment has gained attention. Calcium ions (Ca²⁺) have been identified as essential regulators of NSC physiology, playing a critical role in their proliferation and differentiation. Additionally, folic acid, essential for nervous system development, has been shown to promote NSC proliferation and neuronal differentiation [108]. However, its standalone use is limited by low efficiency and instability. To address these limitations, combining folic acid with metal ions has emerged as a promising strategy to efficiently guide NSC differentiation into cholinergic neurons. Qiu et al. [109] developed calcium folate (CaFO) nanoparticles composed of Ca²⁺ and folic acid for AD treatment (Fig. 16G). Upon endocytosis by NSCs, the CaFO nanoparticles are localized to lysosomes (pH < 5.5), where they dissociate into Ca²⁺ and folic acid due to the acidic conditions (Figs. 16H and I). The released Ca²⁺ acts as a signaling messenger, accelerating NSC differentiation via Ca²⁺-mediated signaling pathways, while folic acid specifically drives the differentiation of NSCs into cholinergic neurons (Fig. 16J and K). These differentiated cholinergic neurons mature, synthesize ACh, and release ACh upon stimulation (Fig. 16L), demonstrating functional neuronal properties. In vivo studies confirmed that CaFO nanoparticles enhanced NSC differentiation into cholinergic neurons and improved spatial memory and cognitive function in AD mice. Through stereotactic injection, NSCs treated with CaFO nanoparticles and transplanted into the hippocampi of AD mice survived (Fig. 16M) and differentiated over four weeks, showing high expression of cholinergic markers like ChAT and Map2 (Fig. 16N). The co-treatment of CaFO and NSCs significantly improved spatial learning, memory, and cognitive abilities in these mice.

Comparative synthesis and translational implications of nanomaterial-based strategies for AD

The current nanomaterial-based strategies for AD can be broadly classified into Aβ-targeting systems, tau-directed platforms, redox-regulating nanomedicines, gene-expression modulators, and stem-cell-related regenerative formulations. Among these, Aβ-targeting approaches remain the most extensively developed because amyloid pathology has long served as a central therapeutic entry point in AD research. These systems often demonstrate strong plaque-targeting capability and measurable improvements in cognition or neuropathology in preclinical models. However, their overall translational significance may be limited by the increasing recognition that amyloid pathology alone does not fully account for disease progression or clinical heterogeneity.

Tau-targeted and gene-regulatory nanoplatforms may offer greater mechanistic relevance to neurodegeneration and disease progression, especially in later-stage AD, but they are still at a comparatively earlier stage of development and frequently face challenges related to delivery precision, intracellular access, and sustained therapeutic control. Redox-restoring nanomaterials and NSC-related strategies provide broader neuroprotective and regenerative potential, yet these benefits may come at the cost of reduced pathological specificity and greater uncertainty regarding long-term safety, reproducibility, and functional durability.

Taken together, the AD literature suggests that the most promising nanotherapeutic direction may involve multi-target strategies capable of simultaneously addressing protein aggregation, oxidative injury, and neuronal dysfunction. Future work should therefore focus on integrated platform design, disease-stage-specific intervention, and more rigorous translational evaluation, including chronic dosing studies, long-term biosafety analysis, and validation in models that better capture the multifactorial nature of human AD.

Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in an abnormally elongated polyglutamine tract in the huntingtin protein [110]. Clinically, HD is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances, all of which together contribute to substantial long-term disability and reduced quality of life [111]. Although current therapeutic approaches can provide limited symptomatic benefit, they do not effectively alter the underlying disease course or prevent progressive neurodegeneration. From the perspective of nanotherapeutic intervention, the most actionable pathological mechanisms in HD include mutant huntingtin (mHTT) expression and aggregation, selective neurodegeneration, impaired autophagy and proteasomal degradation, mitochondrial dysfunction, oxidative stress, excitotoxicity, and axonal/synaptic dysfunction (Fig. 17 and Table 8) [112–117]. These interconnected pathological nodes are especially relevant to nanomedicine because they provide a strong rationale for gene silencing, intracellular delivery, and neuroprotective platform design. With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Fig. 17.

Molecular Mechanisms in HD Pathogenesis. Reproduced with permission from ref [112].

Copyright 2024, MDPI

Table 8.

Pathogenic mechanisms and potential therapeutic targets in HD

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Genetic and protein abnormalities	Mutation in the HTT gene on chromosome 4, leading to CAG repeat expansion (normal ≤ 35; pathogenic ≥ 36); results in an elongated polyglutamine (polyQ) tract	Increased aggregation propensity of mHTT, formation of toxic oligomers and insoluble inclusions in the nucleus and cytoplasm; disruption of normal cellular functions and brain atrophy	HTT-lowering (ASO/siRNA/shRNA), blocking abnormal transcription/splicing, aggregation inhibitors, molecular chaperone enhancement
Neurodegeneration	Selective degeneration of GABAergic MSNs in the striatum, with significant neuronal loss in the cerebral cortex	Basal ganglia circuit disruption, leading to motor, cognitive, and psychiatric symptoms	Neurotrophic support (e.g., enhancing BDNF signaling), synaptic and circuit remodeling strategies, cell replacement/implantation approaches
Mitochondrial dysfunction	mHTT disrupts mitochondrial membrane potential, impairs electron transport chain (ETC) activity, and reduces ATPsynthesis; abnormal mitochondrial permeability transition pore (mPTP) opening releases cytochrome c	Impaired cellular energy production, activation of caspase cascades, and promotion of neuronal apoptosis	Mitochondrial homeostasis regulation (e.g., PGC-1α activation), mPTP inhibition, antioxidants to clear ROS, metabolic support agents
Autophagy and proteasome dysfunction	mHTT impairs autophagy and proteasomal degradation systems, leading to the accumulation of toxic protein aggregates	Accumulation of damaged proteins and organelles inside cells, exacerbating toxicity and neuronal injury	Autophagy/lysosome enhancement (TFEB axis, mTOR/AMPK regulation), UPS function improvement, PROTAC/molecular glue strategies
Excitotoxicity	Excessive glutamatergic activity leads to excessive NMDA receptor (NMDAR) activation, disrupting calcium homeostasis and mitochondrial function	Calcium overload, energy crisis, and neuronal cell death	NMDAR/synaptic plasticity regulation, glutamate reuptake enhancement, calcium homeostasis and downstream pathway intervention
Dopaminergic dysfunction and neuroinflammation	Dopamine system dysregulation and microglial activation lead to excessive production of pro-inflammatory cytokines (e.g., TNF-α, IL-6)	Disrupted neurotransmission, neuroinflammation, and synaptic loss	Inflammation pathway inhibition/immune modulation, microglial function reprogramming, dopaminergic signaling fine-tuning (to avoid exacerbating excitotoxicity)
Axonal and synaptic dysfunction	mHTT interferes with synaptic vesicle trafficking, neurotransmitter release (particularly GABA and glutamate), and dopamine receptor signaling (D1/D2)	Synaptic loss, impaired neuronal communication, motor abnormalities (e.g., chorea)	Axonal transport and microtubule stabilizers, synaptic homeostasis and plasticity enhancers, circuit-specific neuro-modulation

(1) Genetic and Protein Abnormalities

HD is caused by an autosomal dominant mutation in the HTT gene located on chromosome 4, which results in the expansion of the CAG trinucleotide repeat sequence (normal ≤ 35 repeats; pathogenic ≥ 36 repeats) [113]. This leads to the production of a polyglutamine (polyQ) tract at the N-terminus of the huntingtin protein. The mutant huntingtin protein (mHTT) exhibits a higher propensity for aggregation, forming toxic oligomers and insoluble protein aggregates that accumulate in the nucleus and cytoplasm [114]. These aggregates disrupt normal cellular functions and contribute to brain atrophy. Additionally, the expanded CAG sequence may cause aberrant splicing of messenger RNA, generating truncated toxic proteins.

(2) Neurodegeneration

A hallmark of HD is neurodegeneration, primarily in the striatum (caudate nucleus and putamen) and cerebral cortex, which results in approximately 30% brain mass reduction in the later stages [115]. The degeneration predominantly affects GABAergic medium spiny neurons (MSNs) within the striatum, disrupting basal ganglia circuits and leading to the characteristic motor, cognitive, and psychiatric symptoms seen in HD patients.

(3) Mitochondrial Dysfunction

HD patients exhibit significant mitochondrial dysfunction, including impaired metabolic activity, increased oxidative stress, and compromised mitochondrial function. mHTT disrupts mitochondrial membrane potential, impairs electron transport chain (ETC) activity, and reduces ATP synthesis. Additionally, the opening of the mitochondrial permeability transition pore (mPTP) releases cytochrome c, activating caspase cascades and promoting neuronal apoptosis.

(4) Autophagy and Proteasome Dysfunction

mHTT impairs autophagy and proteasomal degradation systems, leading to the accumulation of toxic protein aggregates. Dysfunctional autophagy hampers the cellular clearance of damaged proteins and organelles, exacerbating intracellular toxicity and neuronal injury [116].

(5) Excitotoxicity

Excessive glutamatergic activity contributes to excitotoxicity, which disrupts calcium homeostasis and mitochondrial function, leading to neuronal cell death. Dysregulated glutamate signaling in HD exacerbates neurodegeneration, despite the essential role of glutamate in normal neurotransmission [117].

(6) Dopaminergic Dysfunction and Neuroinflammation

Dopaminergic dysfunction and microglial activation in HD contribute to the excessive production of pro-inflammatory cytokines, such as TNF-α and IL-6, which amplify neuroinflammation and disrupt synaptic activity. Dopamine dysregulation impairs neurotransmission, while activated microglia and astrocytes exacerbate inflammation, leading to neuronal injury and synaptic loss.

(7) Axonal and Synaptic Dysfunction

HD pathology includes impaired axonal transport and synaptic dysfunction, which severely disrupts neuronal communication. mHTT interferes with synaptic vesicle trafficking and neurotransmitter release, especially for GABA and glutamate. Furthermore, dysregulated dopamine receptor signaling (D1/D2) disrupts the integrity of striatal-cortical circuits, contributing to motor abnormalities like chorea and motor initiation deficits.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Targeted suppression of mutant HTT expression using nanomaterials for HD treatment

RNA interference (RNAi) technology has emerged as a promising approach in gene therapy, with siRNA acting as a pivotal molecule for precise regulation of gene expression, offering potential for the treatment of various diseases [118]. In the context of HD, reducing the concentration of mHTT is a central therapeutic strategy, and siRNA plays a crucial role in this process. However, siRNA faces several challenges in clinical applications, such as instability in extracellular environments, difficulty in crossing cell membranes, and the potential to trigger immune responses, which significantly hinder its therapeutic potential. To address these issues, Ellederová and colleagues [119] developed iron oxide magnetic nanoparticles (siRNA-PEI-OA MNPs) for HD treatment. These nanoparticles are composed of a magnetic Fe₃O₄ core, coated with oleic acid (OA), modified with polyethylenimine (PEI), and loaded with siRNA (Fig. 18A). When exposed to an external magnetic field, the Fe₃O₄ core guides the siRNA-PEI-OA MNPs toward the BBB. The OA coating enhances the dispersion and stability of the nanoparticles in physiological environments (Fig. 18B), reducing aggregation and aiding their passage toward the BBB. PEI, a cationic polymer, forms electrostatic complexes with siRNA on the MNP surface. This positive charge not only protects siRNA from enzymatic degradation (Fig. 18C) but also promotes efficient cellular uptake of the nanoparticles. Once the siRNA-PEI-OA MNPs reach the BBB, the combination of magnetic guidance and favorable physicochemical properties facilitates their transport across the BBB via endocytosis (Fig. 18D). The protonatable amino groups in PEI bind to protons in the acidic endosomal environment (pH 5–6), causing osmotic swelling of the endosome. This “proton sponge effect” leads to the rupture of the endosome and the release of siRNA into the cytoplasm. Once inside the cytoplasm, the siRNA forms an RNA-induced silencing complex (RISC) with its target mRNA from the HTT gene. The RISC then cleaves the target mRNA or inhibits its translation, preventing the synthesis of the mutant huntingtin protein.

Fig. 18.

A Schematic representation of MNPs, B TEM micrographs of siRNA-PEI-OA-MNPs, C Agarose gel electrophoresis assay of siRNA-PEI-OA-MNPs, D Confocal microscopy images, E Schematic representation of HTT ASO NDs, F ApoA-I concentrations, G Ex vivo fluorescence imaging of whole brains, H Ex vivo fluorescence imaging of coronally-sectioned brains, I Representative immunoblot, J WB of HTT, K Immunoblots and quantification of mHTT levels. A–D Reproduced with permission from ref [119].

Copyright 2023, American Chemical Society. E–L Reproduced with permission from ref [121]. Copyright 2024, Elsevier

Antisense oligonucleotide (ASO) technology has emerged as a promising therapeutic approach for the treatment of HD. ASOs regulate gene expression by binding specifically to target gene transcripts, inducing RNase H-mediated degradation, and demonstrating potential in reducing mHTT levels [120]. However, a significant challenge for ASO-based therapies is their inability to efficiently cross the BBB, which limits their effectiveness in treating CNS diseases. To address this limitation, Hayden et al. [121] developed apolipoprotein A-I nanodisks (apoA-I NDs), composed of apolipoprotein A-I (apoA-I) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), to facilitate HD therapy (Fig. 18E). ApoA-I NDs self-assemble into stable discoidal structures through interactions between apoA-I and DMPC. The apoA-I component of these nanodisks enables BBB penetration by binding to the scavenger receptor class B type 1 (SR-B1) on endothelial cells of the BBB, facilitating transcytosis independent of clathrin- or caveolin-mediated endocytosis (Fig. 18F). Upon crossing the BBB, apoA-I NDs deliver conjugated HTT-targeting ASOs to neurons and other target cells. The ASOs, designed as gapmers, bind to HTT mRNA and induce RNase H-mediated degradation, leading to the suppression of mHTT production. Following intracerebroventricular (ICV) injection, apoA-I NDs demonstrated widespread distribution in the cortex, striatum, hippocampus, and cerebellum (Fig. 18G and H), resulting in significant mHTT reduction in these brain regions (Fig. 18I–L) as well as in peripheral organs such as the liver, skeletal muscle, and heart, indicating successful ASO delivery to both the CNS and peripheral tissues. This dual-targeting capability offers a novel therapeutic strategy for HD, enabling precise regulation of disease-associated proteins.

Nanomaterial-mediated activation of autophagy through the proteasomal pathway for HD therapy

The core pathological mechanism of HD is the abnormal accumulation of mHTT, which disrupts neuronal function. Within the cellular defense systems against proteinopathies, the autophagy pathway plays a crucial role due to its ability to clear misfolded proteins and damaged organelles through lysosomal degradation, thereby maintaining cellular homeostasis [122]. However, traditional autophagy-targeted therapeutic strategies have faced significant limitations in HD research. To overcome these, Wen and colleagues [123] developed biocompatible manganese ferrite nanoparticles (MnFe₂O₄ NPs) coated with dextran for HD treatment. Although MnFe₂O₄ NPs induced the conversion of Atg8/LC3-I to LC3-II and stimulated autophagy, their primary mechanism of accelerating Htt clearance was through the ubiquitin–proteasome system (UPS). In this process, Ubiquilin-1 acted as a ubiquitin receptor, facilitating the transport of ubiquitinated Htt to the proteasome for degradation. This mechanism led to reduced intracellular accumulation of mutant Htt, alleviated its neurotoxicity, and ultimately exerted therapeutic effects in HD.

Ischemic stroke

Ischemic stroke (IS) is a major cause of mortality and long-term disability and results from abrupt interruption of cerebral blood flow [124]. From the perspective of nanotherapeutic intervention, the most critical pathological events include vascular occlusion and ischemic hypoxia, excitotoxicity, oxidative stress during reperfusion, inflammatory activation, and BBB disruption (Fig. 19 and Table 9). These interconnected processes define the major therapeutic windows for nanomaterials, including thrombolytic delivery, antioxidant protection, anti-inflammatory modulation, and BBB-oriented targeting.

Fig. 19.

Molecular Mechanisms in IS Pathogenesis. Reproduced with permission from ref [125].

Copyright 2024, Elsevier

Table 9.

Major mechanisms of ischemic stroke pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Vascular occlusion and ischemic hypoxia	Occlusion of cerebral arteries reduces or eliminates blood flow, leading to ischemic hypoxia and rapid depletion of ATP, impairing cellular metabolism and ion homeostasis	Depletion of oxygen and nutrients, leading to neuronal injury, cellular dysfunction, and death	Targeting thrombolytic therapies to restore blood flow, enhancing oxygen and nutrient delivery to the ischemic region
Glutamate excitotoxicity	Excessive glutamate release coupled with impaired reuptake leads to elevated extracellular glutamate levels, overactivation of NMDA and AMPA receptors, and massive intracellular calcium influx	Calcium overload in neurons triggers protease and kinase activation, destabilizing cellular integrity and promoting neuronal apoptosis and necrosis	NMDA receptor antagonists, AMPA receptor modulators, or glutamate reuptake inhibitors to prevent excitotoxicity
Oxidative stress and reperfusion injury	Mitochondrial dysfunction following ischemia and reperfusion increases ROS generation, overwhelming antioxidant defenses, causing oxidative damage to cellular structures and activating apoptotic/necrotic pathways	Oxidative damage to lipids, proteins, and DNA, with exacerbation of BBB disruption, inflammation, and tissue injury, creating a vicious cycle of damage	Antioxidant therapies targeting ROS, and inhibitors of apoptotic and necrotic pathways to reduce oxidative damage and neuronal death
Inflammatory response	Release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β) activates microglia, which shift to a pro-inflammatory M1 phenotype, while peripheral macrophages exacerbate inflammation	Exacerbation of ischemic damage through continued inflammation, leukocyte infiltration, and further BBB damage	Anti-inflammatory agents targeting pro-inflammatory cytokines (TNF-α, IL-1β), and modulation of microglial activation (M1 to M2 phenotype)
BBB disruption	Endothelial dysfunction during reperfusion increases vesicular transport, leading to BBB disruption, immune cell infiltration, and the release of neurotoxic factors	Increased permeability of the BBB, immune cell infiltration, and neurotoxic factor release, contributing to sustained neuronal injury and neuroinflammation	Pharmacological agents to restore BBB integrity, limit endothelial dysfunction, and prevent immune cell infiltration

(1) Vascular Occlusion and Ischemic Hypoxia

Arterial occlusion rapidly deprives brain tissue of oxygen and glucose, leading to ATP depletion, ionic imbalance, and early neuronal injury. This stage is particularly relevant to thrombolytic and perfusion-restoring nanocarriers.

(2) Glutamate Excitotoxicity

Excess glutamate release and impaired reuptake cause overactivation of NMDA and AMPA receptors, resulting in calcium overload and neuronal death. This provides a rationale for nanoplatforms that reduce excitotoxic signaling or protect vulnerable neurons [126].

(3) Oxidative Stress and Reperfusion Injury

Reperfusion further amplifies ROS production, mitochondrial dysfunction, and oxidative damage to proteins, lipids, and DNA. Antioxidant and nanozyme-based systems are therefore highly relevant in IS therapy.

(4) Inflammatory Response

Activated microglia, infiltrating macrophages, and pro-inflammatory cytokines exacerbate tissue injury and BBB breakdown [127]. This makes post-stroke inflammation an important target for immunomodulatory nanomedicine.

(5) BBB Disruption

Endothelial injury and inflammatory mediators compromise BBB integrity, promoting edema and immune-cell infiltration. At the same time, this disruption creates both a challenge and an opportunity for brain-targeted nanotherapeutic delivery.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-mediated thrombolysis for IS treatment

Ischemic Stroke, one of the leading global causes of disability and mortality, has long been a focus of medical research and therapeutic development [128]. While traditional thrombolytic therapy, such as recombinant tissue plasminogen activator (tPA), has shown promise for clinical improvement, existing drugs face several limitations, including a short half-life and risks such as hemorrhage and cerebral edema. These issues often lead to poor patient prognosis. As a result, targeted thrombolytic strategies have emerged as a critical area of research aimed at enhancing treatment efficacy for ischemic stroke.

In this context, Zhao and colleagues [129] recently reported a novel tPA delivery platform (APLT-PA), utilizing Annexin V and platelet membranes. This system consists of three key components: platelet membranes fused with liposomes via extrusion, tPA encapsulated within the core, and Annexin V surface modifications. The APLT-PA platform was specifically designed for the treatment of acute ischemic stroke. This system achieves thrombus-targeted delivery through interactions between platelet membrane proteins and thrombotic sites, particularly via Annexin V binding to phosphatidylserine exposed on activated platelet membranes. Upon reaching the thrombotic site, the encapsulated tPA converts soluble plasminogen into insoluble plasmin, initiating fibrinolysis in response to stimuli such as activated platelets. Tail vein injection of APLT-PA in acute ischemic stroke mouse models demonstrated significant fluorescence accumulation at thrombotic regions, confirming the system’s strong targeting and accumulation capabilities. Laser speckle imaging revealed marked restoration of blood flow in occluded vessels. Additionally, behavioral assessments showed substantial improvements in motor function and neurological recovery within 7 days post-administration.

Tissue plasminogen activator (tPA) faces several clinical limitations, including the risk of adverse events and insufficient control over oxidative damage caused by excessive ROS during reperfusion. This oxidative stress exacerbates inflammatory responses and leads to poor patient outcomes. To address these challenges, Fan et al. [130] developed an innovative peptide-templated manganese dioxide nanozyme (PNzyme/MnO₂) through biomineralization. This nanozyme integrates two engineered peptides with MnO₂ nanoparticles that mimic the enzymatic activities of superoxide dismutase (SOD) and CAT, enabling simultaneous thrombolytic therapy and ROS scavenging in ischemic stroke (Fig. 20A). Functional peptide 1 contains four key domains: a fibrin-binding CREKA sequence for thrombus targeting, a thrombin-cleavable linker (LTPRGWRLGGC) for controlled peptide release, a transferrin receptor-binding HAIYPRH motif for BBB penetration, and a hydrophobic metal-binding domain for stabilization. Functional peptide 2 includes an ischemic neuron-targeting CLEVSRKNC sequence and a complementary metal-binding domain for structural assembly. This multi-stage targeting system demonstrates several layers of targeting capability. During BBB transit, peptide 1’s HAIYPRH motif binds to endothelial transferrin receptors, initiating receptor-mediated transcytosis (Fig. 20B). Upon BBB penetration, the CLEVSRKNC sequence in peptide 2 directs accumulation at ischemic neurons (Fig. 20C). At thrombus sites, the CREKA domain ensures fibrin-specific localization. Thrombin cleavage of the LTPRGWRLGGC linker releases the active thrombolytic peptide (GRPAK) to initiate clot dissolution (Figs. 20D and E). Concurrently, the MnO₂ core scavenges ROS generated during thrombolysis and reperfusion, mitigating oxidative stress and neuronal apoptosis through synergistic SOD-CAT mimetic activity. After intravenous administration, PNzyme/MnO₂ demonstrated selective BBB crossing and targeted fibrin-rich microthrombus accumulation in rat embolic stroke models. Treatment significantly reduced infarct volumes compared to controls, from 58.9 ± 4.2% to 42.1 ± 3.8% (p < 0.01; Fig. 20F). Similar neuroprotective effects were observed in mouse transient middle cerebral artery occlusion (MCAO) models, with infarct volume decreasing from 34.7 ± 2.1% to 19.3 ± 1.8% (p < 0.001). These results confirm the dual therapeutic efficacy of PNzyme/MnO₂ through precision thrombolysis and ROS clearance. This nanozyme platform overcomes key limitations of conventional tPA therapy by integrating thrombus-targeted drug delivery, controlled thrombolytic activation, and multi-enzyme antioxidant protection, providing a promising translational approach for ischemic stroke management.

Fig. 20.

A Schematic illustration of PNzyme/MnO₂, B The ratio of various formulations traversing the BBB in vitro, C Localization of PNzyme/MnO₂ in cells, D Cleavage of thrombin-responsive peptide after incubation with thrombin, E Fibrin clot lysis assay by the agar plate method, F TTC staining of rat brain slices from the embolic stroke models, G Schematic illustration of BNN6-DiR, H In vitro thrombus-targeting fluorescence intensity in artificial blood clots, I images of carotid artery thrombotic vessels, J NO release curves, K Images of blood clots, L Representative fluorescence images. A–F Reproduced with permission from ref [130].

Copyright 2023, Wiley–VCH GmbH. G–H Reproduced with permission from ref [131]. Copyright 2023, Springer Nature

The powerful propulsion of nanomotors enables deep thrombus penetration, offering a unique advantage over conventional therapies. This enhanced penetration capacity not only significantly improves thrombolytic efficacy but also elevates the therapeutic potential for ischemic stroke, establishing a solid foundation for novel, efficient, and safe therapeutic strategies. Luo and colleagues [131] recently reported the development of self-propelled nanomotors (T-BD NAs) featuring high fuel loading and controllable motion capabilities for ischemic stroke therapy (Fig. 20G). These nanomotors incorporate a photothermal sensitizer (DiR) and a photoactivatable NO donor (BNN6), with surface modifications using DSPE-PEG2K for enhanced stability and DSPE-PEG-CREKA for thrombus targeting. The T-BD NAs demonstrated specific accumulation at thrombus sites through CREKA peptide-mediated targeting (Fig. 20H). Upon 808 nm laser irradiation (2 W/cm²), the photothermal conversion of DiR raised the local temperature beyond 50 °C (Fig. 20I), effectively disrupting non-covalent fibrin bonds to loosen the thrombus structure and facilitate thrombolysis. Concurrently, laser irradiation activated NO release from BNN6 (Fig. 20J), producing bifunctional therapeutic effects: NO-mediated propulsion powered by NO thrust enhanced nanomotor penetration into thrombus depths, while cGMP-dependent platelet inactivation via suppressed aggregation and concomitant microvascular network repair synergistically prevented neo-thrombosis and restored cerebral perfusion in ischemic regions. The synergistic combination of DiR-mediated photothermal thrombolysis and NO-driven mechanical disruption significantly increased fibrin/hemoglobin levels in the supernatant and reduced thrombus volume (Figs. 20K). Following intravenous administration in rat middle cerebral artery occlusion (MCAO) models, T-BD NAs exhibited targeted accumulation significantly surpassing control groups (Fig. 20L). This approach achieved a remarkable reduction in infarction rate to 5%, substantially lower than previously reported values of 10–20%, demonstrating exceptional potential for thrombus resolution and cerebral ischemia mitigation.

Nanomaterial-based anti-inflammatory and antioxidant strategies for IS therapy

In the pathological progression of ischemic stroke, excessive ROS production leads to oxidative damage, severely impacting cerebrovascular structures and neuronal networks. This makes ROS a critical therapeutic target [132].

Traditional treatments for ischemic stroke, such as the free radical scavenger edaravone, demonstrate partial efficacy but are hindered by poor BBB penetration, requiring repeated high doses and resulting in significant adverse effects. To overcome these limitations, Shi et al. [133] developed an innovative ischemic stroke therapeutic agent (E-A/P-CeO₂), which combines monodisperse ceria nanoparticles loaded with edaravone and functionalized with Angiopep-2-PEG modifications for targeted cerebroprotection in ischemic stroke treatment. The E-A/P-CeO₂ nanoparticles traverse the BBB through Angiopep-2-mediated binding to the low-density lipoprotein receptor-related protein (LRP) overexpressed on cerebrovascular endothelial cells, facilitating targeted accumulation at the thrombotic site. At the lesion site, the fluorite-structured ceria core scavenges ROS via reversible Ce³⁺/Ce⁴⁺ redox cycling, generating oxygen vacancies through electron transfer. This antioxidant activity is synergistically enhanced by the co-delivery of edaravone, enabling dual-pathway ROS elimination. Following tail vein injection, E-A/P-CeO2 demonstrated efficient BBB penetration with substantial brain accumulation. At the optimal dose (0.6 mg/kg), cerebral infarct volume was reduced from 45.6 ± 4.8% (control) to 15.0 ± 4.1%. Concurrently, ROS levels were significantly reduced, indicating effective oxidative stress mitigation and therapeutic efficacy in ischemic stroke treatment.

Wang et al. [134] developed an engineered hyaluronic acid hydrogel (PLGA/VEGF-loaded HA-AC hydrogel), which combines Pluronic F127 (PF127) nanoparticles loaded with 6-bromoindirubin-3’-oxime (BIO), a glycogen synthase kinase 3β (GSK3β) inhibitor, porous poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating vascular endothelial growth factor (VEGF), and modified hyaluronic acid (HA-AC) hydrogel. This system is designed for sequential dual-drug delivery with distinct release kinetics to treat ischemic stroke (Fig. 21A). In the cerebral infarct region, the HA-AC hydrogel, which mimics the native extracellular matrix (ECM), bypasses the BBB and transports the encapsulated PF127/BIO nanoparticles and PLGA/VEGF microspheres to the ischemic site. Due to the small particle size and micellar structure of PF127 nanoparticles, BIO was rapidly released, achieving an 80% cumulative release within 3 days (Fig. 21B). This rapid release effectively addresses early-stage inflammatory responses. The released BIO exerts anti-inflammatory effects by inhibiting microglial polarization toward the pro-inflammatory M1 phenotype (as indicated by reduced CD86 + microglia; Fig. 21C) and promoting polarization toward the anti-inflammatory M2 phenotype (evidenced by increased CD163 + microglia; Fig. 21D). This process also involves the suppression of TLR4-mediated NF-κB and MAPK signaling pathways, thereby reducing apoptosis. As the PLGA microspheres undergo ester bond degradation, VEGF is gradually released, reaching a cumulative release of 50% over 15 days. This sustained VEGF release stimulates vascular endothelial cell proliferation and angiogenesis (Fig. 21E). When administered via stereotaxic injection into ischemic stroke mouse models, the hydrogel mitigated inflammatory cell infiltration, upregulated vascular basement membrane proteins (e.g., collagen IV), and improved motor, sensory, balance, and reflex functions. These improvements were evidenced by behavioral assessments, including the modified neurological severity score (mNSS), cylinder test, and grid-walking test (Fig. 21F).

Fig. 21.

A Schematic illustration of injectable hydrogels, B The cumulative release, C The number of CD86 + microglial cells, D Representative double immunofluorescence images, E Representative images of tubular networks in Matrigel, F The grid test was conducted to assess foot faults, G Schematic illustration of synthesis of T-mPDA-Pep-Mino nanosystem, H Fluorescence intensity ratio changes of CD206 vs CD86, I Morphological observation of BV-2 cells, J Evaluation of ·OH scavenging, K Ex vivo fluorescence imaging of brains and brain slices, L Representative TTC staining images, M Expression of IL-10 in brain. A–F Reproduced with permission from ref [134].

Copyright 2022, Elsevier. G–M Reproduced with permission from ref [135]. Copyright 2023, Springer Nature

In the pathological progression of IS, neuroinflammation and oxidative stress are pivotal factors contributing to neuronal damage and cell death, thus exacerbating the disease. The dynamic changes in neuroinflammation, along with the excessive accumulation of ROS, worsen the ischemic condition. Consequently, developing effective anti-inflammatory and antioxidant strategies has become a crucial research focus for ischemic stroke treatment. Chen et al. [135] developed a polydopamine-based nanosystem, termed T-mPDA-Pep-Mino, which integrates mesoporous polydopamine as its core component. This system is conjugated with an MMP-2-responsive peptide linked to minocycline (Pep-Mino) and a polyethylene glycolylated brain-targeting peptide (PEG-RAP-12) for sequential drug delivery to treat ischemic stroke (Fig. 21G). The PEG-RAP-12 moiety exhibits high affinity for the low-density lipoprotein receptor-related protein 1 (LRP-1) on the BBB, facilitating receptor-mediated transcytosis, which ensures targeted delivery of the nanosystem into the brain. Once the system reaches the brain microenvironment, the over-activated microglia secrete MMP-2, which cleaves the Pep-Mino linkage, triggering the controlled release of minocycline. This release inhibits the pro-inflammatory polarization of microglia via modulation of the NF-κB pathway (Figs. 21H and I). Simultaneously, the mesoporous polydopamine core effectively scavenges ROS (e.g., ·OH, ·O₂^⁻, and H₂O₂), mitigating oxidative neuronal damage (Fig. 21J). Upon tail-vein administration, fluorescence tracking revealed that the T-mPDA-Pep-Mino nanoparticles accumulated in the mouse brains, with peak levels at 4 h and sustained elevated concentrations for the next 72 h (Fig. 21K). This therapeutic intervention significantly reduced cerebral infarct volume in middle cerebral artery occlusion (MCAO) model mice compared to the saline controls (Fig. 21L). Moreover, it effectively downregulated pro-inflammatory cytokines (IL-1β, IL-6) and upregulated anti-inflammatory mediators (IL-4, IL-10) (Fig. 21M). Notably, the treatment group exhibited substantial improvements in motor, sensory, reflex, and balance functions, demonstrating enhanced functional recovery.

Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurrent seizures arising from abnormal neuronal hyperexcitability and pathological network synchronization. Although currently available antiepileptic therapies can suppress seizures in many patients, a substantial proportion remain drug-resistant, and existing treatments often fail to adequately address the mechanisms that drive epileptogenesis and long-term neuronal dysfunction. From the perspective of nanotherapeutic intervention, the most actionable pathological mechanisms in epilepsy include excitation–inhibition imbalance, GABAergic and glutamatergic dysregulation, circuit hyperexcitability, synaptic dysfunction, neuroinflammation, oxidative stress, and ion-channel-related abnormalities (Table 10) [136]. These interconnected mechanisms are especially relevant to nanomedicine because they define multiple opportunities for improving brain delivery, modulating neurotransmission, reducing inflammatory injury, and restoring network stability. With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Table 10.

Major mechanisms of epilepsy pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Excitation–inhibition imbalance	Reduced GABAergic inhibition (e.g., loss of parvalbumin-expressing interneurons); increased glutamatergic activity	Network hyperexcitability; spread of seizures across brain regions	GABAergic enhancers (e.g., Benzodiazepines, Vigabatrin); Glutamate receptor antagonists (e.g., AMPA/Kainate inhibitors)
Synaptic dysfunction	Impaired GABAergic signaling (GABA_A and GABA_B receptor dysfunction); glutamate receptor changes (NMDA, AMPA)	Disruption of synaptic plasticity; loss of synaptic homeostasis	Modulators of synaptic proteins (SHANK3, NRXN); NMDA receptor antagonists (e.g., Memantine, Ketamine)
Glutamatergic overactivity	Hyperactivity in glutamatergic neurons, especially excitatory projections; upregulation of glutamate receptors	Excessive neuronal firing; amplification of seizure activity	Excessive neuronal firing; amplification of seizure activity
GABAergic dysfunction	Reduced function of inhibitory interneurons (PV, SST), dysregulation of GABAergic signaling pathways	Increased neuronal firing and network synchronization; seizure generation	Increased neuronal firing and network synchronization; seizure generation
Neuromodulatory systems alterations	Dysregulated cholinergic, serotonergic, dopaminergic, and noradrenergic systems	Altered neuronal excitability and brain arousal state; increased seizure susceptibility	Neuromodulatory agents (5-HT receptor agonists, Dopamine precursors); Vagus nerve stimulation (VNS)
Glial cell involvement	Microglial activation, reactive astrocytosis, and inflammatory cytokine release (e.g., IL-6, TNF-α)	Neuroinflammation; disruption of ionic homeostasis; exacerbation of epileptogenesis	Anti-inflammatory agents (Minocycline, Corticosteroids); Microglial modulators (P2X7 receptor inhibitors)
Network hyperconnectivity	Enhanced connectivity in epileptogenic circuits; altered long-range brain connectivity (cortex, hippocampus)	Impaired communication between brain regions; increased seizure propagation	Impaired communication between brain regions; increased seizure propagation
Ion channel dysfunction	Abnormalities in ion channel function (e.g., Nav1.1, Kv7, KCNQ2 mutations)	Disturbed action potentials; loss of cellular homeostasis; neuronal hyperexcitability	Ion channel modulators (Phenytoin, Lamotrigine); Genetic therapies targeting ion channels (Gene editing CRISPR)
Excitatory circuit propagation	Overactivation of excitatory circuits, particularly the hippocampus, cortex, and thalamus	Seizure spread across the brain; network synchronization and seizure persistence	Targeted deep brain stimulation (DBS); Network disconnection strategies (e.g., Anterior thalamus DBS)

(1) Excitation–Inhibition Imbalance and Network Hyperexcitability

A hallmark of epilepsy is the disruption of the excitation-inhibition (E/I) balance within neural circuits. In healthy brains, excitatory neurotransmitters like glutamate and inhibitory neurotransmitters such as GABA maintain a delicate balance that ensures proper neuronal function [137]. However, in epilepsy, this balance is disturbed, with reduced inhibition of excitatory glutamatergic neurons. This results in excessive neuronal firing, which can spread across brain regions, leading to generalized seizures [138]. This network hyperexcitability is often linked to specific brain regions, such as the cortex, hippocampus, and thalamus, which are all implicated in seizure propagation.

(2) Alterations in GABAergic and Glutamatergic Neurons

GABAergic interneurons play a critical role in controlling the spread of excitation in the brain. These cells, particularly parvalbumin (PV)-expressing neurons, normally exert inhibitory control over excitatory neurons, such as pyramidal cells. However, in epilepsy, dysfunction in GABAergic signaling leads to impaired inhibition, facilitating the onset and propagation of seizures. Conversely, glutamatergic neurons, especially those with long-range projections, are often hyperactive during seizures, amplifying the excitatory drive that contributes to seizure generation [139].

Interestingly, the role of these neurons may vary depending on the seizure’s stage and the specific neural circuit involved. For example, activation of certain glutamatergic circuits may inhibit seizure activity, while others may exacerbate it. This dual role of glutamatergic circuits highlights the complexity of seizure dynamics and the need for precise therapeutic targeting.

(3) Long-Range Neural Circuitry and Projection Pathways

Epileptic seizures can spread throughout the brain via long-range projections from both GABAergic and glutamatergic neurons. These long-range circuits form the foundation for how seizures propagate across distinct brain regions. Notably, some glutamatergic projections may exert opposing effects on seizure activity. For instance, projections from the entorhinal cortex to the hippocampus have an inhibitory effect, reducing the severity of seizures, while other circuits originating from the same brain regions may enhance seizure activity.

(4) Neuromodulatory Systems in Epilepsy

Neuromodulatory systems, including cholinergic, serotonergic, dopaminergic, and noradrenergic pathways, play significant roles in modulating neuronal excitability. These systems influence the overall state of the brain, affecting how susceptible an individual is to seizures. For example, cholinergic signals from the basal forebrain enhance inhibitory activity within the hippocampus, helping to control seizure activity. Similarly, serotonin and dopamine influence the brain’s arousal and seizure susceptibility, with altered activity in these systems being linked to epilepsy. The therapeutic potential of neuromodulation is supported by evidence showing that activating or inhibiting specific neuromodulatory circuits can reduce seizure frequency and severity.

(5) Glial Cells and Inflammatory Responses

Glial cells, such as astrocytes and microglia, are increasingly recognized for their role in epilepsy. These cells help regulate the extracellular environment, maintain E/I balance, and contribute to synaptic plasticity. In epileptic brains, glial cell dysfunction can exacerbate neuronal hyperexcitability by failing to maintain proper ionic balance or by contributing to neuroinflammation. Inflammation, particularly in response to seizure activity, can worsen neuronal damage and promote epileptogenesis [140].

The pathophysiology of epilepsy is multifactorial, involving dysfunction at the cellular, circuit, and network levels. A combination of reduced inhibition, increased excitation, altered neuronal signaling, and glial involvement all contribute to the initiation and progression of seizures.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-based strategies for restoring excitatory-inhibitory balance and modulating network hyperexcitability in epilepsy therapy

Among the pathological mechanisms of epilepsy, excitation–inhibition imbalance represents one of the most central therapeutic entry points for nanomaterial-based intervention. Fang et al. [141] reported the development of a TiS₂/Pt nanotransducer, composed of few-layer titanium disulfide (TiS₂) and platinum (Pt) nanoparticles, for the treatment of epilepsy. The TiS₂/Pt nanotransducer is introduced into the brain by stereotactic injection into the hippocampus of mice. Once in the brain, the TiS₂ component of the nanotransducer modulates neuronal activity through near-infrared light-induced photothermal stimulation, altering the membrane capacitance of neurons. This induces calcium influx and triggers neuronal excitability, reducing the abnormal high-frequency neuronal discharges associated with epilepsy. At the same time, Pt’s enzyme-like activity neutralizes ROS produced during seizures, reducing oxidative stress and restoring redox balance in the brain. This dual mechanism of neuromodulation and neuroprotection helps restore the balance between excitatory and inhibitory neurotransmission. After intravenous injection into an epileptic mouse model, the nanomaterial demonstrated significant therapeutic effects, such as decreased seizure frequency, reduced neuronal hyperexcitability, and restored motor function.

Nanomaterial-based strategies for modulating GABAergic and glutamatergic neurotransmission in epilepsy therapy

Epilepsy is a complex neurological disorder characterized by recurrent seizures, which arise from abnormal neuronal hyperexcitability and imbalances in neurotransmitter systems. A critical factor in the pathophysiology of epilepsy is the disruption between excitatory and inhibitory neurotransmission, particularly within glutamatergic and GABAergic systems. Glutamate, the major excitatory neurotransmitter, and GABA (gamma-aminobutyric acid), the primary inhibitory neurotransmitter, play pivotal roles in maintaining neuronal excitability and preventing seizure activity [142]. In epilepsy, this balance is often disturbed, with increased glutamatergic excitation and reduced GABAergic inhibition, leading to neuronal hyperactivity and seizure propagation. Restoring the delicate equilibrium between excitatory (glutamatergic) and inhibitory (GABAergic) signaling is therefore a critical therapeutic target for controlling seizures and improving patient outcomes. Oxidative stress and neuroinflammation exacerbate this imbalance, further destabilizing the excitability of neuronal networks.

Targeting oxidative stress while simultaneously modulating GABAergic and glutamatergic systems holds significant promise in correcting these imbalances and providing a more effective strategy for epilepsy treatment. Liu and colleagues [143] reported the development of an α-lipoic acid-based nanozyme (LA@PHT-Ca²⁺ nanozyme), formed through UV-triggered ring-opening polymerization of α-lipoic acid (LA). This nanozyme self-assembles into core–shell nanocarriers that encapsulate the antiepileptic drug PHT. These nanozymes are stabilized by coordinating with calcium ions (Ca²⁺) via the carboxyl groups of LA, enhancing the therapeutic effect for acute epilepsy treatment. The LA@PHT-Ca²⁺ nanozyme leverages LA’s natural coenzyme properties and is efficiently taken up by brain microvascular endothelial cells (bEnd.3) and hippocampal cells through sodium-dependent multivitamin transporters (SMVT), enabling it to cross the BBB. Once in the brain, LA’s sulfur-containing structure confers strong reducing properties, exhibiting SOD-like (superoxide dismutase-like) and POD-like (peroxidase-like) enzymatic activities. This allows the nanozyme to clear O₂⁻·, H₂O₂, and ·OH through a cascade of redox reactions, alleviating oxidative stress and stabilizing mitochondrial energy states, while providing antioxidant protection to neurons. Importantly, the LA-based nanozyme not only reduces oxidative stress but also impacts the GABAergic and glutamatergic neurotransmitter systems. By alleviating oxidative damage, the nanozyme indirectly supports the restoration of GABAergic inhibition and glutamatergic excitation, thereby helping to re-establish the balance between excitatory and inhibitory signaling in the brain. This balance is critical for controlling seizure activity and preventing hyperexcitability. Additionally, Ca²⁺, as a coordinating agent, interacts with the carboxyl groups of LA to modify the surface potential and stabilize the nanoparticle structure. This interaction disrupts mitochondrial oxidative phosphorylation (OXPHOS), reduces ATP levels, and inhibits the Hif-1α/Abcb1 (P-gp) signaling axis, decreasing drug efflux and extending the intracellular retention time of PHT. After intravenous injection into an epileptic rat model, significant therapeutic improvements were observed, including delayed seizure onset, shortened seizure duration, reduced seizure frequency, and decreased EEG excitability. These outcomes were accompanied by the restoration of neurotransmitter balance, particularly the enhancement of GABAergic inhibition and the reduction of excessive glutamatergic excitation. As a classic sodium channel blocker, PHT, when combined with the LA-based carrier, not only enhances the drug’s retention time in the brain but also amplifies its antiepileptic effects by modulating the GABAergic and glutamatergic systems, thus offering a more comprehensive approach to treating epilepsy.

Nanomaterial-mediated modulation of long-range neural circuits and projection pathways for epilepsy therapy

Excessive neuroinflammation is a core pathological feature of epilepsy, driven in part by the aberrant activation of microglia and astrocytes. Seizure-related metabolic stress and ionic disequilibrium trigger microglial activation, which amplifies focal inflammation and excitotoxicity through pro-inflammatory mediators such as IL-1β, IL-6, TNF-α, and the NLRP3 inflammasome. This results in a positive feedback loop of “inflammation–hyperexcitability”, which promotes network hypersynchrony and stabilizes epileptogenic circuits. In parallel, inflammation disrupts BBB permeability, allowing peripheral immune signals to enter the brain and exacerbating the difficulty of sustained, lesion-targeted anti-inflammatory therapy [144]. Consequently, a strategy that focuses on breaking the seizure–inflammation–circuit instability loop through targeted modulation of long-range neural circuits and projection pathways is essential for advancing epilepsy treatment.

DAPK1 (Death-Associated Protein Kinase 1) is a key regulator of inflammation and neuronal apoptosis. Its activation enhances neuroinflammation by promoting pro-inflammatory cytokine production via NF-κB and p38/JNK signaling. In epilepsy, DAPK1 sustains the inflammatory cascade, contributing to neuronal hyperexcitability and cell death. Inhibiting DAPK1 disrupts these pathways, reduces inflammation, and protects neurons from excitotoxicity and apoptosis, making it a promising target for treating epilepsy. Zhao et al. [145] reported on macrophage-membrane–camouflaged nanoparticles (MA@RT-HMSNs), which are composed of a macrophage membrane (MA) coating on a hollow mesoporous silica core (HMSNs). These nanoparticles co-load the DAPK1 inhibitor TC-DAPK6 and the tracer dye rhodamine B (RhB) for treating epilepsy. The macrophage membrane facilitates inflammation-homing and adherence to receptors on microglia, enabling MA@RT-HMSNs to cross the BBB and actively accumulate at seizure foci. Within the epileptic lesion, the HMSN core provides a sustained release of TC-DAPK6, inhibiting DAPK1 activity. This in turn dampens NF-κB and p38/JNK signaling, reducing the expression of IL-1β, IL-6, and TNF-α. This cascade of anti-inflammatory effects suppresses the overactivation of Iba1-positive microglia and GFAP-positive astrocytes, limits NLRP3 inflammasome activation, and curtails neuronal apoptosis, ultimately preserving neuronal structure and function. Importantly, the inflammatory signaling cascade that is modulated by MA@RT-HMSNs helps in re-establishing the functional integrity of long-range neural circuits and prevents hyperexcitability across brain regions, stabilizing the neural networks involved in seizure propagation. Following intravenous injection, enhanced fluorescence in the cortex and hippocampus is observed within 1–24 h, indicating the successful enrichment of nanoparticles in the epileptic regions. Treatment with MA@RT-HMSNs significantly decreases seizure frequency, alleviates inflammation and gliosis, and improves cognitive functions, motor performance, and anxiety-related behaviors. More importantly, the modulation of inflammatory pathways and neural circuits offers a comprehensive approach to treating epilepsy by breaking the cycle of inflammation-induced hyperexcitability and restoring the balance of long-range neural projections.

Nanomaterial-mediated regulation of neuroinflammation and microglial function for epilepsy treatment

Epilepsy is a complex neurological disorder commonly associated with neuroinflammation, particularly the excessive activation of microglial cells and astrocytes. These glial cells play a crucial role during epileptic seizures by releasing pro-inflammatory cytokines (such as IL-1β and TNF-α) and reactive oxygen species (ROS), which exacerbate neuronal damage and pathological changes, creating a vicious cycle that further aggravates the condition. Thus, modulating glial cell activity and controlling neuroinflammation are key to epilepsy treatment. Liu et al. [146] reported a dual-functional system, Lipo-HFn, composed of a liposome part, Lipo@RepSOX, and a heavy-chain ferritin part, HFn@IPA, loaded with indolepropionic acid (IPA), for the treatment of epilepsy. In Lipo-HFn, the heavy-chain ferritin (HFn) targets the transferrin receptor 1 (TfR1) highly expressed on the endothelial cells of the BBB, allowing it to cross the BBB. Once inside the brain, the acidic environment of the endosome/lysosome disrupts the electrostatic interactions between Lipo@RepSOX and HFn@IPA, leading to their dissociation. RepSOX inhibits the ALK5 and TGF-β signaling pathways, enhancing the expression of tight junction proteins (such as Claudin-5 and ZO-1), thereby repairing and stabilizing the damaged BBB. This reduces the permeability of the BBB, preventing harmful substances from entering the brain, improving microvascular stability, and alleviating the pathological changes of epilepsy and other brain diseases. After dissociation, HFn@IPA enters the brain parenchyma, where IPA inhibits the excessive activation of microglial cells and astrocytes, reducing the secretion of pro-inflammatory cytokines (such as IL-1β and TNF-α) and alleviating neuroinflammation. Additionally, IPA scavenges ROS, reducing oxidative stress-induced neuronal damage, protecting nerve cells, and repairing the neuroinflammation caused by epilepsy. After intravenous injection, Lipo-HFn enters the epileptic mouse model and, over time, demonstrates significant therapeutic effects, including a marked reduction in seizure frequency and an extension of seizure latency.

In recent years, the importance of microglia in the pathogenesis of epilepsy has gradually gained attention. As immune cells in the brain, microglia not only participate in immune responses but also play a crucial role in neuroinflammation [142]. During the pathological process of epilepsy, microglia become excessively activated, releasing various pro-inflammatory factors, which exacerbates neuronal damage. Modulating the function of microglia and inhibiting their excessive inflammatory response has emerged as a promising strategy for the treatment of epilepsy. Ding et al. [147] reported the use of a coordination acid-engineered Prussian Blue (PB@ZIF) nanosystem, composed of Prussian Blue (PB) as the core and zeolitic imidazolate framework (ZIF-8) as the shell, for the treatment of epilepsy. Microglia, as immune cells in the brain, have strong phagocytic abilities and can recognize and clear foreign substances. As a result, PB@ZIF can be effectively internalized and exert its therapeutic effect in the brain. Once inside the brain, PB, as the core, exhibits significant free radical scavenging capabilities, effectively alleviating oxidative stress-induced damage, restoring microglial homeostasis, reducing neuronal injury, and improving epilepsy symptoms by inhibiting glycolytic reprogramming and inflammatory responses. ZIF-8, as the shell, not only enhances PB’s reactivity but also significantly increases its catalytic efficiency by modulating the local acidic environment, thereby improving its free radical scavenging effectiveness and further enhancing the therapeutic effect. After intravenous injection, PB@ZIF accumulates in microglia in the brain of the model mice and achieves significant therapeutic effects within 24 h, reducing the frequency and duration of seizures and improving memory deficits and anxiety symptoms.

Depression

Major depressive disorder (MDD) is a multifactorial psychiatric disorder shaped by interacting biological and environmental influences [148]. Although its pathogenesis cannot be explained by a single hypothesis, several mechanisms are especially relevant to nanotherapeutic intervention, including neurotransmitter imbalance, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, neuroinflammation, oxidative stress, and impaired neuroplasticity (Fig. 22 and Table 11). These mechanisms are of particular interest because they not only contribute to depressive symptoms, but also define the principal biological targets through which nanomaterials may improve brain delivery, enhance therapeutic retention, and enable more mechanism-oriented treatment.

Fig. 22.

Molecular Mechanisms in MDD Pathogenesis. Reproduced with permission from ref [149].

Copyright 2024, Springer Nature

Table 11.

Major mechanisms of depression pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Neurotransmitter imbalance and receptor dysfunction	Dysregulation of 5-HT, DA, NE neurotransmitter systems and astrocytic modulation of synaptic activity	Mood dysregulation, cognitive dysfunction, emotional instability, and impaired synaptic plasticity	SNRIs, dopamine agonists, and modulation of astrocytic function
HPA axis dysfunction	Chronic activation of HPA axis, leading to excessive release of cortisol and CRH, disrupting hippocampal and prefrontal cortex functions	Neuronal atrophy, impaired memory formation, and emotional dysregulation	Glucocorticoid receptor antagonists, modulation of the HPA axis, and neuroprotective agents
Inflammation and immune dysregulation	Elevation of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), oxidative stress, and activation of the NLRP3 inflammasome	Neuroinflammation, glutamate excitotoxicity, and exacerbation of depressive symptoms	Anti-inflammatory cytokine therapies, antioxidants, and inflammasome inhibitors
Glial cell dysfunction	Reduced astrocyte density and dysfunction, impaired glutamate clearance, excitotoxicity, and altered E/I balance	Decreased neurogenesis, impaired synaptic activity, and emotional disturbances	Neuroplasticity-enhancing agents, glutamate modulators, and astrocytic-targeting therapies
Genetic and epigenetic factors	Identification of over 100 genetic loci linked to MDD susceptibility (e.g., SLC6A4, GRIK5, BDNF) and epigenetic modifications due to environmental stress	Increased genetic susceptibility, disrupted neurodevelopment, and stress sensitivity	Gene therapy, epigenetic modification, and personalized treatment based on genetic profiles
Neuroplasticity and synaptic remodeling	Impairment of hippocampal neurogenesis, reduction in BDNF levels, and decreased synaptic plasticity due to chronic stress and elevated glucocorticoids	Cognitive and emotional dysfunction, loss of synaptic connections, and impaired brain plasticity	Neurogenesis-promoting agents, BDNF modulators, and brain stimulation therapies
Gut-brain axis dysregulation	Dysbiosis in gut microbiota influencing serotonin metabolism and systemic inflammation crossing the blood–brain barrier	Increased inflammation, altered neurotransmitter metabolism, and exacerbation of depression symptoms	Probiotics, prebiotics, and gut-brain axis modulation therapies

(1) Neurotransmitter Imbalance and Receptor Dysfunction

Dysregulation of serotonin, dopamine, and norepinephrine remains a core mechanism in MDD, contributing to mood instability, anhedonia, and cognitive dysfunction [150, 151]. In addition, glial regulation of neurotransmitter availability and synaptic signaling has received increasing attention. These pathways are especially relevant to nanomedicine because many antidepressant nanoplatforms are designed to improve CNS delivery and sustained modulation of monoaminergic signaling.

(2) Hypothalamic–Pituitary–Adrenal (HPA) Axis Dysfunction

Chronic stress-induced hyperactivation of the HPA axis leads to excessive glucocorticoid exposure, which impairs hippocampal and prefrontal cortical function and disrupts neurogenesis and synaptic plasticity [152]. This stress-related biological axis is relevant to nanotherapeutic design because it links peripheral endocrine dysregulation with central neurobiological injury.

(3) Inflammation and Immune Dysregulation

An increasing body of evidence supports the cytokine hypothesis of depression, proposing that neuroinflammation plays a significant role in the development of MDD. Proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 are elevated in the brains of individuals with depression [153]. These cytokines activate the NLRP3 inflammasome, leading to further inflammatory cascades that exacerbate depressive symptoms. The presence of oxidative stress (OS), particularly the imbalance between antioxidants and ROS, also contributes to neuronal damage and depression onset.

(4) Glial Cell Dysfunction

Astrocytes, the principal glial cells in the brain, play a key role in maintaining synaptic homeostasis and facilitating neuroplasticity [154]. In MDD, a reduction in astrocyte density and dysfunction in astrocyte-neuron interactions have been observed. These changes affect the glutamate-glutamine cycle, leading to excitotoxicity and synaptic loss. Additionally, astrocytic dysfunction impairs the clearance of excess glutamate, contributing to the excitatory/inhibitory (E/I) imbalance observed in MDD. Alterations in glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4), markers of astrocyte function, have been linked to the severity of depressive symptoms.

(5) Genetic and Epigenetic Factors

Genetic predisposition plays a crucial role in MDD, with heritability estimates ranging between 30–50%. Over 100 genetic loci associated with neurotransmitter function, synaptic plasticity, and neurodevelopmental processes have been identified. Key genes, such as SLC6A4 (serotonin transporter), GRIK5 (glutamate receptor), and BDNF (brain-derived neurotrophic factor), have been implicated in depression susceptibility [155]. Recent advancements in epigenetics have further elucidated how environmental factors, such as stress, may interact with genetic susceptibility to promote depression.

(6) Neuroplasticity and Synaptic Remodeling

Neuroplasticity, particularly hippocampal neurogenesis, is severely impaired in individuals with MDD. Decreased levels of BDNF, a critical regulator of neuroplasticity, are commonly observed. Chronic stress and elevated glucocorticoid levels lead to the reduction of BDNF expression and synaptic remodeling in the hippocampus, prefrontal cortex, and amygdala, all of which contribute to the cognitive and emotional dysfunction seen in MDD [156]. Pharmacological treatments that enhance neuroplasticity, such as SSRIs, have been shown to promote synaptic regeneration and improve depressive symptoms.

(7) Gut-Brain Axis Dysregulation

Emerging research highlights the role of the gut microbiota in modulating brain function through the gut-brain axis. Dysbiosis, or imbalance in gut bacteria, has been linked to depression. Alterations in microbiota composition can affect the metabolism of tryptophan, a precursor to serotonin, and disrupt the production of neuroactive metabolites, exacerbating depressive symptoms [157]. Additionally, systemic inflammation caused by gut dysbiosis can cross the blood–brain barrier, further contributing to neuroinflammation and depression.

Overall, the pathophysiology of MDD involves convergent abnormalities in neurotransmission, stress signaling, inflammation, and neuroplasticity, all of which provide biologically meaningful entry points for nanomaterial-based intervention.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-mediated precision modulation of neurotransmitter imbalance for targeted depression therapy

Depression, a major global public health concern, profoundly affects patients’ quality of life and mental-physical well-being, thus making the development of effective therapeutic strategies a central focus of research. Among various proposed pathogenic mechanisms, the dysfunction of monoamine neurotransmitters, particularly 5-HT, has attracted significant attention.

Fluoxetine (FLX), a widely used selective 5-HT reuptake inhibitor (SSRI), alleviates depressive symptoms by inhibiting presynaptic 5-HT transporters (SERT), thereby increasing synaptic 5-HT concentrations [158]. Despite its widespread clinical use, conventional FLX therapy faces a critical limitation: delayed onset of action. This delay not only increases the risk of suicide during the early treatment phase but also reduces patient adherence. To address these issues, novel drug delivery systems have emerged as an innovative platform. Lin et al. [159] developed a tetrahedral DNA nanostructure (TDN)-based drug delivery system, TDNs@FLX, combining tetrahedral DNA nanostructures with fluoxetine for depression therapy. TDNs effectively targeted the brain regions affected by depression, delivering fluoxetine in a controlled manner to achieve localized therapeutic concentrations. As an SSRI, fluoxetine inhibits presynaptic SERT, reducing synaptic 5-HT reuptake and elevating 5-HT levels to ameliorate depressive symptoms. Notably, during the early stages of treatment, TDNs@FLX synergistically promoted the proliferation of neural progenitor cells in the hippocampal dentate gyrus and enhanced neuronal plasticity, accelerating symptom relief and shortening the delayed onset typically observed with traditional antidepressants. Following intravenous administration, fluorescence signals of TDNs@FLX appeared in brain tissue within 10 min and peaked at 40 min, demonstrating its robust brain-targeting capability. After two weeks of treatment, TDNs@FLX-treated depressive mice exhibited significant improvements, including weight recovery, alleviation of psychomotor retardation, reduced despair behaviors (such as decreased immobility time in forced swim tests), and restored hedonic responsiveness. These therapeutic effects persisted throughout the 4-week treatment period.

The stability of the monoamine neurotransmitter system is essential for maintaining normal emotional and cognitive functions, with monoamine oxidases (MAOs) playing a central role in regulating this balance. MAOs metabolize monoamine neurotransmitters such as 5-HT, dopamine (DA), and norepinephrine (NE). Abnormal MAO activity disrupts this equilibrium, triggering a cascade of depressive symptoms [160]. While conventional antidepressant therapies aim to modulate monoamine neurotransmitter levels, their clinical efficacy is limited due to their inability to effectively regulate MAO activity and their challenges in crossing the BBB. To address these challenges, Shi and colleagues [161] developed a novel nanoplatform BRH (BP-RVG29@HYP), which consists of black phosphorus nanosheets (BP), the neuron-targeting peptide RVG29, and the antidepressant hypericin (HYP), for the treatment of depression (Fig. 23A). RVG29 specifically binds to nAChR on the BBB and neuronal cells, facilitating BRH transcytosis across brain capillary endothelial cells. Additionally, 808 nm NIR irradiation reduces the expression of the tight junction protein Claudin-5 in the BBB (Fig. 23B), thereby enhancing BRH penetration into the brain (Fig. 23C). Within the BRH system, HYP serves as the primary therapeutic agent by inhibiting MAO activity and modulating neurotransmitter metabolism. It regulates the synaptic uptake of gamma-aminobutyric acid (GABA) and L-glutamate while upregulating the expression of 5-HT receptors (5-HT1A and 5-HT2A), which are essential for neurotransmission. Concurrently, BP nanosheets scavenge ROS, alleviating oxidative stress and protecting neurons from damage. After intravenous injection, fluorescence signals in the NIR-irradiated BP-RVG29@HYP group were detectable in the brain within 2 h, peaked at 4 h, and remained visible at 24 h (Fig. 23D). In depressive model mice treated with NIR-irradiated BP-RVG29@HYP, brain levels of 5-HT, DA, and NE were significantly elevated (Fig. 23E–G), accompanied by substantial improvements in depressive-like behaviors.

Fig. 23.

A schematic of BP-RVG29@HYP, B Effects of different treatments on the tight junction protein Claudin-5, C X–Z vertical confocal micrographs, D In vivo whole-body fluorescence imaging, E the antidepressant effect in the experimental group, F Contents of 5-HT, G Contents of DE. A–F Reproduced with permission from ref [161].

Copyright 2024 Wiley‐VCH GmbH

Comparative synthesis and translational implications of nanomaterial-based strategies for depression

Compared with the nanomedicine literature on neurodegenerative disorders, nanomaterial-based interventions for depression remain relatively limited in number and are more strongly concentrated on improving brain delivery, enhancing antidepressant bioavailability, and modulating neurotransmitter imbalance, oxidative stress, or neuroinflammation. This translational orientation is a practical strength, because many depression-related nanoplatforms are built around clinically familiar drugs or bioactive molecules, making them more immediately relevant to therapeutic optimization.

At the same time, this apparent practicality also reveals an important limitation: many currently reported systems function primarily as advanced delivery carriers rather than as truly mechanism-driven nanotherapeutics tailored to the biological heterogeneity of depression. While redox-modulating, anti-inflammatory, and neurotransmission-regulating platforms show encouraging antidepressant-like effects in behavioral models, disease-specific molecular targeting remains less developed than in disorders such as PD or AD. Furthermore, many studies rely on acute or stress-based rodent models that only partially recapitulate the chronic, heterogeneous, and clinically stratified nature of human depression.

Therefore, the most promising future direction for depression nanomedicine lies not only in improving drug transport across the BBB, but also in integrating delivery engineering with biologically informed target selection. Future studies should emphasize subtype-relevant mechanisms, long-term safety, sex-dependent effects, and standardized translational endpoints to better determine which nanoplatforms are most likely to generate clinically meaningful benefit.

Schizophrenia

Schizophrenia is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment, arising from complex interactions among genetic susceptibility, neurotransmitter dysregulation, neurodevelopmental abnormalities, immune activation, and environmental stressors [162, 163]. Although current antipsychotic therapies can alleviate certain manifestations of the disease, particularly those associated with dopaminergic hyperactivity, they often provide limited benefit for negative and cognitive symptoms and do not correct the underlying biological heterogeneity of schizophrenia. From the perspective of nanotherapeutic intervention, the most actionable pathological mechanisms in schizophrenia include genetic and epigenetic dysregulation, dopamine- and glutamate-related signaling abnormalities, neurodevelopmental disruption, neuroinflammation, and impaired synaptic plasticity (Table 12) [164]. These interconnected pathological nodes are particularly relevant to nanomedicine because they provide a rationale for both mechanism-oriented intervention and improved central nervous system delivery of neuroactive agents. With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Table 12.

Major mechanisms of schizophrenia pathogenesis and their therapeutic targets

Mechanism category	Key mechanisms	Clinical manifestations	Molecular/Cellular mechanisms
Genetic susceptibility	Multiple susceptibility genes (e.g., COMT, DISC1, NRG1)	Increased familial risk, significant heritability	Genetic variations affect synaptic function and neurodevelopment, particularly impacting dopamine and glutamate systems
Neurotransmitter imbalance	Dopamine Hypothesis, Glutamate Hypothesis, GABA system dysfunction	Positive symptoms (hallucinations, delusions), negative symptoms (flattened affect, social withdrawal), cognitive deficits (working memory impairment)	Dopamine hyperactivity in the mesolimbic pathway causes positive symptoms; NMDA receptor dysfunction affects glutamatergic signaling, contributing to negative and cognitive symptoms
Neurodevelopmental disruptions	Abnormalities in neuronal proliferation, migration, differentiation, and synapse formation	Reduced gray matter, hippocampal atrophy, impaired neural connectivity	Genetic predispositions and environmental factors during early brain development compromise neural circuits
Immune and inflammatory mechanisms	Elevated pro-inflammatory cytokines (IL-6, TNF-α), maternal infections	Chronic neuroinflammation, possible disruption of blood–brain barrier integrity	Microglial activation and immune dysregulation interfere with synaptic plasticity and exacerbate schizophrenia symptoms
Epigenetic regulation	DNA methylation, histone acetylation, non-coding RNA regulation	Persistent changes in gene expression, affecting neuroplasticity and synaptic connectivity	Environmental factors modify gene expression via epigenetic mechanisms, leading to alterations in neurodevelopment and neurotransmission

(1) Genetic Vulnerabilities and Epigenetic Regulation

Schizophrenia has a strong heritable component [164], and susceptibility genes such as COMT, DISC1, and NRG1 are implicated in synaptic development and neurotransmitter regulation [165, 166]. These pathways are highly relevant to nanomedicine because they provide potential targets for gene- and epigenome-oriented intervention.

(2) Neurotransmitter Imbalance

Dopamine hyperactivity is closely associated with positive symptoms, whereas glutamatergic and GABAergic dysfunction contribute more strongly to negative and cognitive symptoms. This imbalance provides the rationale for nanocarriers designed to optimize CNS delivery of antipsychotic and neuromodulatory agents [167–170].

(3) Neurodevelopmental Disruptions

Abnormal neuronal proliferation, migration, differentiation, and synapse formation during development can compromise neural circuit maturation and long-term connectivity [171]. These developmental mechanisms are important because they suggest that precision delivery strategies may eventually need to move beyond symptomatic dopamine regulation alone [172, 173].

(4) Immune Dysregulation and Inflammation

Elevated inflammatory cytokines and microglial activation have been linked to schizophrenia pathogenesis and may further disrupt BBB integrity and synaptic function [174]. This supports the inclusion of neuroinflammatory modulation as an emerging nanotherapeutic direction.

(5) Synaptic Plasticity and Brain Network Dysfunction

Impaired synaptic plasticity and disrupted connectivity in the prefrontal cortex and hippocampus contribute to persistent cognitive dysfunction [175]. These abnormalities highlight the need for future nanoplatforms that address circuit-level and cognitive outcomes rather than only psychotic symptoms [176].

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-mediated epigenome editing for precision medicine in schizophrenia therapy

The strong association between vasoactive intestinal peptide receptor 2 (VIPR2) gene microduplications and the pathogenesis of schizophrenia has been well established through multiple genome-wide studies [177]. This genetic linkage, first identified in 2011 through large-scale copy number variation (CNV) analyses, has positioned VIPR2-selective antagonists as promising therapeutic candidates for schizophrenia. However, the development of the peptide antagonist KS-133 – a potent bicyclic compound with nanomolar-range VIPR2 selectivity – faces two critical challenges: BBB penetration and a lack of in vivo validation in schizophrenia models.

To overcome these limitations, Miyako et al. [178] reported a novel drug delivery system (DDS)-based formulation, KS-133/KS-487 nanoparticles (ICG-KS-133/KS-487 NPs). These nanoparticles consist of the KS-133 peptide (a VIPR2-selective antagonist) and the NIR fluorescent dye indocyanine green (ICG), with the surface modified by the KS-487 peptide, which binds to low-density lipoprotein receptor-related protein 1 (LRP1) to facilitate BBB penetration. The KS-487 peptide on the surface of the ICG-KS-133/KS-487 nanoparticles adopt a loop-helix structure, binding to the cluster IV domain of LRP1 on the BBB. The binding of amino acid residues such as Tyr6 and Lys7 on KS-487 facilitates the transport of these nanoparticles from peripheral tissues into the brain via receptor-mediated transcytosis (RMT). Once the nanoparticles reach the diseased site, KS-133, as a VIPR2-selective antagonist, inhibits VIPR2 activity, thereby reducing downstream signaling caused by excessive VIPR2 activation. This regulation helps normalize the abnormal activities of related neural pathways and improves cognitive dysfunction in schizophrenia mouse models. Following intravenous injection, significant fluorescence from ICG was observed in the brains of mice at 48 h. After continuous treatment with ICG-KS-133/KS-487 nanoparticles for two weeks, the cognitive ability of the schizophrenia model mice was significantly improved compared to the control group.

Nanomaterial-mediated regulation of dopamine function for schizophrenia treatment

Dopamine, a pivotal neurotransmitter in the brain, plays a crucial role in the pathogenesis of schizophrenia. Extensive evidence has highlighted significant abnormalities within the dopamine system in individuals with schizophrenia, opening up potential therapeutic avenues targeting dopamine regulation. Modulating dopamine function has therefore become a key therapeutic strategy to enhance the efficacy of schizophrenia treatments [179, 180].

Hoare and colleagues [181] developed an innovative drug delivery system (DDS) based on in-situ gelling nanoparticle network hydrogels composed of oxidized starch nanoparticles (SNP-CHO) and carboxymethyl chitosan (CMCh) to deliver the dopamine D2 receptor positive allosteric modulator, PAOPA, for schizophrenia treatment. Upon intranasal administration, the aldehyde groups on SNP-CHO interacted with the abundant primary amine groups in CMCh, forming Schiff bases that not only linked SNP-CHO and CMCh but also induced in-situ gelation. This gelation process ensured high retention rates on the nasal mucosa. Over time, the hydrogel gradually degraded due to enzymatic activity from bioactive substances in the nasal mucosa and interstitial fluid. During the degradation process, PAOPA-loaded SNP-CHO particles crossed the nasal epithelium through mechanisms such as active transport and were subsequently carried along the olfactory and trigeminal nerves to the brain. At the lesion site, PAOPA, a positive allosteric modulator of the dopamine D2 receptor, exerted its therapeutic effects by interacting with dysregulated dopamine D2 receptors. This interaction induced conformational changes in the receptors, enhanced dopamine binding, and regulated downstream signaling pathways, ultimately normalizing neural signal transmission and alleviating the symptoms of schizophrenia. Fluorescence imaging revealed that after intravenous injection, the nanoparticles exhibited significant fluorescence in the brain within 48 h. After 5 days of treatment, the social interaction time in the MK-801-induced schizophrenia model rats significantly increased in the treatment group compared to the control, effectively ameliorating the behavioral abnormalities associated with schizophrenia.

Comparative synthesis and translational implications of nanomaterial-based strategies for schizophrenia

The currently available nanomaterial-based strategies for schizophrenia are mainly concentrated in two directions: precision modulation of disease-relevant gene regulation and enhanced delivery of antipsychotic or neuroactive agents targeting dopaminergic dysfunction. Gene- and epigenome-oriented platforms are conceptually attractive because they align with the emerging view of schizophrenia as a disorder involving genetic vulnerability, neurodevelopmental disruption, and long-term regulatory imbalance. However, these approaches remain highly experimental and face substantial translational barriers, including delivery complexity, uncertain persistence of biological effects, and limited safety evidence for long-term application in the central nervous system.

By contrast, nanocarrier-based systems for regulating dopamine-related pathways or improving intranasal delivery of antipsychotic compounds may be closer to practical therapeutic implementation, since they often build upon already recognized pharmacological mechanisms [182, 183]. Their main advantages include improved bioavailability, reduced peripheral exposure, and the potential to mitigate adverse effects associated with conventional administration routes. Nevertheless, these formulations still do not fully address the multidimensional pathology of schizophrenia, particularly the negative and cognitive symptoms linked to glutamatergic dysfunction, synaptic abnormalities, and neurodevelopmental deficits.

Overall, the schizophrenia literature indicates that nanomedicine in this field is promising but still mechanistically narrow. Future progress will likely require broader target diversification beyond dopamine-centered strategies, together with rigorous evaluation of long-term safety, brain distribution, cognitive outcomes, and clinical applicability in biologically relevant models.

Insomnia

Insomnia is a multifactorial neuropsychiatric disorder characterized by difficulty initiating or maintaining sleep, often accompanied by impaired daytime function and persistent hyperarousal. Although currently available hypnotic and sedative therapies can provide short-term symptomatic relief, their long-term use may be limited by tolerance, dependence, residual sedation, and incomplete correction of the underlying biological disturbances associated with chronic insomnia. From the perspective of nanotherapeutic intervention, the most actionable pathological mechanisms in insomnia include GABAergic and glutamatergic imbalance, serotonergic dysregulation, dopaminergic hyperarousal, chronic hypothalamic–pituitary–adrenal (HPA) axis overactivation, and neuroinflammation (Table 13). These interconnected mechanisms are especially relevant to nanomedicine because they define opportunities for controlled release, improved brain-targeted delivery, prolonged therapeutic retention, and more precise modulation of sleep-regulating pathways. With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Table 13.

Major mechanisms of insomnia pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
GABA-glutamate imbalance	Altered GABAergic signaling leads to cortical-thalamic-limbic hyperactivation and neuronal excitability, impairing sleep initiation and maintenance	Increased cerebral excitability disrupts sleep–wake transitions and stability, leading to insomnia	GABAergic signaling modulators, NMDA receptor antagonists, and glutamate reuptake inhibitors
5-HT dysregulation	Dysregulation of 5-HT signaling disrupts sleep–wake switching and enhances cognitive and emotional arousal	Impaired serotonergic function prolongs wakefulness and exacerbates emotional arousal, aggravating insomnia	Selective 5-HT reuptake inhibitors (SSRIs) and 5-HT receptor modulators
Dopaminergic hyperarousal	Elevated dopamine levels promote wakefulness, suppressing sleep and contributing to hyperarousal	Heightened arousal and inability to initiate or maintain sleep are central to the insomnia pathophysiology	Dopamine receptor antagonists and dopamine release modulators
Chronic hyperactivation of the HPA axis	Chronic activation of the HPA axis leads to hypercortisolemia, disrupting nocturnal cortisol rhythms and impairing NREM sleep processes	Dysregulated cortisol rhythms interfere with sleep processes, worsening insomnia severity	Pharmacological agents targeting cortisol production, glucocorticoid receptors, and HPA axis modulation
Neuroinflammation	Pro-inflammatory cytokines (e.g., IL-6, TNF-α) activate microglia, which enhance cognitive arousal and contribute to sleep fragmentation	Microglial activation and inflammation lead to cognitive arousal, sleep fragmentation, and further worsening of insomnia	Anti-inflammatory drugs targeting cytokine production (e.g., IL-6, TNF-α inhibitors) and microglial activation
Genetic susceptibility	Polymorphisms in circadian genes (e.g., CLOCK, PER3) and abnormal epigenetic modifications (e.g., BDNF gene promoter hypermethylation) increase susceptibility to insomnia	Increased genetic susceptibility and epigenetic alterations amplify vulnerability to chronic insomnia	Circadian rhythm modulators, epigenetic therapy targeting BDNF gene expression
Gut-brain axis dysregulation	Gut microbiota metabolites, particularly SCFAs, modulate 5-HT biosynthesis and BBB permeability, affecting sleep regulation	Dysregulation of gut-brain communication leads to reduced treatment efficacy in some insomnia cases	Gut microbiota modulation using probiotics, prebiotics, or SCFAs to influence 5-HT synthesis

(1) Neurotransmitter Dysregulation

GABA-Glutamate Imbalance: A central pathological feature of insomnia is an imbalance between GABAergic inhibition and glutamatergic excitation. GABA, the primary inhibitory neurotransmitter, plays a crucial role in maintaining the sleep–wake cycle. In patients with insomnia, altered GABAergic signaling—resulting from dysfunction in its synthesis, release, or receptor activity—reduces its inhibitory effects. This leads to cortical-thalamic-limbic hyperactivation and increased cerebral excitability, impairing both sleep initiation and maintenance. In contrast, glutamate, the principal excitatory neurotransmitter, antagonizes GABAergic signaling. Excessive glutamate release activates NMDA receptors, causing neuronal hyperexcitability, which destabilizes sleep onset and continuity.

5-HT Dysregulation: 5-HT plays a dual role in regulating sleep–wake dynamics by promoting wakefulness and suppressing REM sleep. Dysfunction in the serotonergic system disrupts the mechanisms responsible for sleep–wake switching, particularly by impairing sleep-promoting signals from the ventrolateral preoptic nucleus (VLPO). Reduced serotonergic transmission decreases inhibition of noradrenergic neurons in the locus coeruleus, thereby prolonging wakefulness. Additionally, 5-HT dysregulation in brain regions such as the hippocampus and amygdala—critical for memory consolidation and emotional regulation—further exacerbates sleep disturbances by enhancing cognitive and emotional arousal. 5-HT also influences cortical excitability and sleep–wake transitions through complex interactions with the pontine-mesencephalic reticular formation, a key component of the ascending reticular activating system (ARAS).

Dopaminergic Hyperarousal: Elevated DA levels are associated with heightened arousal, promoting wakefulness and suppressing sleep. This hyperarousal contributes significantly to the pathophysiology of insomnia.

(2) Chronic Hyperactivation of the HPA Axis

Chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis is central to the development of insomnia. Stress-induced hypercortisolemia suppresses melatonin secretion and continually activates stress responses by downregulating glucocorticoid receptor sensitivity, particularly in the hippocampus. Dysregulated nocturnal cortisol rhythms interfere with slow-wave oscillations and sleep spindles during non-rapid eye movement (NREM) sleep, thereby exacerbating the severity of insomnia.

(3) Neuroinflammation

Elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, induce microglial activation, which enhances functional connectivity in prefrontal-limbic circuits. These inflammatory processes increase cognitive arousal, contributing to sleep fragmentation and reinforcing the pathological mechanisms of insomnia.

(4) Genetic Susceptibility

Molecular genetic studies have revealed significant associations between polymorphisms in circadian rhythm-related genes, such as CLOCK and PER3, and increased vulnerability to insomnia. Additionally, abnormal epigenetic modifications, such as hypermethylation of the brain-derived neurotrophic factor (BDNF) gene promoter, impair synaptic plasticity and disrupt sleep-dependent memory consolidation, thereby amplifying susceptibility to insomnia.

(5) Gut-Brain Axis Dysregulation

Gut microbiota metabolites, particularly short-chain fatty acids (SCFAs), modulate the tryptophan-kynurenine metabolic pathway, which in turn influences 5-HT biosynthesis and BBB permeability. This bidirectional gut-brain communication plays a critical role in explaining the reduced therapeutic responsiveness to conventional pharmacological treatments observed in certain chronic insomnia cases.

Collectively, these multifaceted disruptions lead to persistent hyperarousal, characterized by an imbalance between arousal-promoting neuronal circuits (e.g., the locus coeruleus and hypothalamic orexin neurons) and sleep-promoting circuits (e.g., the VLPO and basal forebrain). This pathophysiological state perpetuates sleep disturbances and complicates therapeutic interventions, highlighting the need for targeted therapeutic strategies that address these specific pathological mechanisms.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-mediated GABA regulation for insomnia treatment

Insomnia, a widespread sleep disorder in modern society, severely affects individuals’ daily lives and their physical and mental health, necessitating a focused investigation into its underlying mechanisms [184]. Gamma-aminobutyric acid (GABA), a critical inhibitory neurotransmitter in the central nervous system (CNS), plays a vital role in regulating the sleep–wake cycle. By binding to its receptors, GABA promotes neuronal relaxation, reducing cerebral excitability and facilitating the initiation and maintenance of sleep.

Zaleplon, a widely used non-benzodiazepine hypnotic, exerts sedative effects by selectively binding to the α-1, β-2, and γ-2 subunits of the GABA_A receptors in the CNS, enhancing GABAergic inhibition and thereby lowering neuronal excitability to induce sleep. However, zaleplon’s short half-life limits its effectiveness in maintaining sleep, and its significant first-pass effect and low oral bioavailability diminish its therapeutic efficacy. Recent advances in nanotechnology-based drug delivery systems present forward-looking strategies to address these limitations. Chang et al. [185] introduced an innovative intranasal gel delivery system (PEG-SWCNTs-Z) for insomnia treatment, which incorporated zaleplon-loaded single-walled carbon nanotubes (SWCNTs) functionalized with DSPE-PEG5000-NH2 (Fig. 24A). To ensure prolonged absorption without disrupting normal breathing during sleep, PEG-SWCNTs-Z were embedded in a carbomer gel responsive to the ionic environment of nasal fluids. Upon nasal administration, the carbomer gel transitioned into a free-flowing liquid in the presence of nasal fluid ions (Fig. 24B and C), enabling efficient penetration of the PEG-SWCNTs-Z through the nasal mucosa and subsequent entry into the systemic circulation via abundant capillaries. The needle-like structure of SWCNTs facilitated the transport of zaleplon across the BBB. Within the brain, zaleplon was gradually released over the first 4 h (Fig. 24D). Released zaleplon selectively bound to the α-1, β-2, and γ-2 subunits of the GABA_A receptors, potentiating receptor activity. This enhanced GABAergic inhibition promoted neuronal relaxation, reduced cerebral hyperexcitability, and supported both sleep onset and maintenance, effectively mitigating insomnia. Simultaneously, the neuroprotective properties of SWCNTs helped maintain neuronal homeostasis, further augmenting zaleplon’s therapeutic effects. After intranasal PEG-SWCNTs-Z administration, fluorescence tracking revealed significantly elevated serum GABA levels, while 5-HT and DA levels were reduced compared to other treatment groups (Figs. 24E–G). Notably, the treatment led to a marked suppression of locomotor activity, demonstrating sedation and hypnotic efficacy comparable to commercially available hypnotic drugs.

Fig. 24.

A Schematic diagram of PEG-SWCNTs-Z, B TEM image of PEG-SWCNTs-Z suspension, C Carbomer 940 gel with different concentrations into liquid, D The drug release curve, E serum concentrations of GABA, F serum concentrations of 5-HT, G serum concentrations of DA. A–G Reproduced with permission from ref [185].

Copyright 2022, Elsevier

Nanomaterial-mediated 5-HT regulation for insomnia treatment

5-HT plays a crucial role in the regulation of sleep. The synthesis, release, and metabolism of 5-HT are involved in modulating the sleep–wake cycle. To improve insomnia, many studies have focused on regulating 5-HT levels to restore normal sleep patterns. In recent years, nanomaterials have emerged as an important strategy for insomnia treatment due to their excellent drug delivery and controlled release properties. Specifically, the use of sustained-release systems to regulate the release of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), enhances 5-HT synthesis and subsequently modulates the sleep–wake cycle. Tian et al. [186] reported a food-based sustained-release system (5-HTP/β-CD/CS NPs) composed of β-cyclodextrin (β-CD) and corn starch (CS) encapsulating 5-HTP for the treatment of insomnia. β-CD, as a drug carrier, has excellent encapsulation ability, improving the solubility and stability of 5-HTP. CS, with its biocompatibility and controlled release properties, ensures the slow release of 5-HTP in the gastrointestinal tract, providing sustained pharmacological effects. After oral administration, the 5-HTP/β-CD/CS NPs are absorbed through the gastrointestinal tract and enter the bloodstream. Once in the brain, 5-HTP is converted to 5-HT by tryptophan hydroxylase (TPH), which increases the concentration of 5-HT in the brain. 5-HT regulates the secretion of melatonin from the pineal gland, thereby modulating the sleep–wake cycle and effectively improving insomnia symptoms. Following treatment with 5-HTP/β-CD/CS NPs, cognitive behaviors and circadian rhythms in the insomnia animal model showed significant improvements, outperforming traditional treatments such as fluoxetine and direct 5-HTP administration. Therefore, 5-HTP/β-CD/CS NPs not only effectively alleviate insomnia symptoms but also improve sleep quality and circadian rhythm by increasing 5-HT levels, offering a novel approach for the treatment of insomnia.

Comparative synthesis and translational implications of nanomaterial-based strategies for insomnia

Nanomaterial-based interventions for insomnia are still at an early stage and are currently dominated by formulations designed to regulate GABAergic and serotonergic signaling or to improve the controlled release and brain accessibility of sleep-promoting compounds. Compared with nanotherapeutic strategies for major neurodegenerative diseases, these systems are generally simpler in design and more directly linked to symptom relief, which may enhance their translational attractiveness in the near term.

However, this symptom-oriented focus also reflects a major limitation of the current literature. Most available platforms primarily optimize pharmacokinetics or administration efficiency rather than addressing the broader pathophysiological network of insomnia, including HPA-axis dysregulation, neuroinflammation, circadian disruption, and hyperarousal-related neural circuit abnormalities. In addition, the experimental evidence remains relatively sparse, and studies often rely on short-term outcome measures without sufficient assessment of long-term safety, tolerance, or rebound effects.

Thus, while existing nanoplatforms for insomnia suggest useful opportunities for improving delivery and sustained efficacy, the field remains underdeveloped at the mechanistic level. Future research should integrate symptom control with disease-relevant biological pathways and establish more robust translational criteria, including chronic-administration safety, sleep architecture analysis, and comparisons with standard clinical therapies.

Autism spectrum disorder

Autism Spectrum Disorder (ASD) is a multifactorial neurodevelopmental condition characterized by impairments in social interaction and communication, as well as repetitive or stereotyped behaviors. Its pathophysiology reflects complex interactions among genetic, molecular, neurobiological, immune, and environmental factors, leading to abnormalities in neural circuits, synaptic plasticity, and brain connectivity (Table 14).

Table 14.

Major mechanisms of ASD pathogenesis and their therapeutic targets

Mechanism	Molecular events	Pathological consequences	Potential therapeutic targets
Genetic and epigenetic alterations	De novo and inherited variants in SHANK3, SCN2A, CHD8, MECP2, TSC1/2, UBE3A; copy-number changes at 16p11.2, 15q11–13, 22q11.2; abnormal DNA methylation, histone marks, and non-coding RNA regulation	Disrupted gene expression programs during brain development; impaired synapse formation and maintenance; increased biological heterogeneity across individuals	Gene and RNA therapies; locus-specific epigenetic editing; small-molecule epigenetic modulators; genotype-guided precision interventions
Synaptic dysfunction and neural circuit imbalance	Altered E/I balance with reduced GABAergic tone (↓GAD1/2; GABA_A/B receptor changes); glutamatergic abnormalities (NMDA/AMPA/mGluR signaling); defects in synaptic adhesion/scaffolding (NRXN–NLGN–SHANK complex); abnormal spine density and plasticity (LTP/LTD)	Network hyperexcitability; abnormal sensory processing; deficits in social communication, learning, and flexibility	GABAergic enhancers; modulators of glutamate receptors (e.g., mGluR5 antagonists, NMDA modulators); stabilizers of synaptic scaffolds; circuit-level neuromodulation (TMS/tDCS) and targeted behavioral training
Dysregulated signal transduction pathways	Hyperactive mTOR–PI3K/AKT; altered MAPK/ERK and Wnt/β-catenin signaling; impaired autophagy and synaptic pruning; excessive activity-dependent protein synthesis	Aberrant neuronal growth and connectivity; defective synaptic maturation; reduced adaptability of neural circuits	mTOR inhibitors (e.g., rapamycin/everolimus in appropriate genetic contexts); PI3K/AKT and MAPK pathway modulators; Wnt pathway regulators; autophagy enhancers; IGF-1 pathway agents in defined syndromic subtypes
Immune and neuroinflammatory responses	Microglial and astrocyte activation; elevated cytokines (IL-6, TNF-α, IL-17); complement-mediated synapse tagging (C1q/C3); maternal immune activation; gut microbiota dysbiosis	Excess or mistimed synaptic pruning; chronic low-grade neuroinflammation; disrupted circuit maturation and function	Anti-inflammatory strategies and cytokine-targeted approaches; microglia-modulating agents; complement pathway modulation; microbiota-directed interventions (diet, pre/probiotics)
Neuroanatomical and connectivity abnormalities	Atypical cortical development (thickness, minicolumns); cerebellar Purkinje cell loss; hippocampal/amygdala changes; altered white-matter integrity (DTI); long-range hypoconnectivity with local hyperconnectivity	Inefficient information transfer between social-cognitive networks; motor and sensorimotor integration deficits; variability in symptom severity	Connectivity-guided rehabilitation; sensory integration therapy; targeted cognitive training; non-invasive brain stimulation aligned to network deficits

(1) Genetic and Epigenetic Alterations

ASD exhibits high heritability, with estimates ranging from 50 to 90%. Over 600 genes have been implicated, many of which are critical for synaptic formation, chromatin remodeling, and transcriptional regulation. High-impact variants, such as mutations in SHANK3, MECP2, TSC1/2, and SCN2A, disrupt synaptic signaling and cortical development. Additionally, epigenetic dysregulation, including altered DNA methylation and histone modifications, further modifies gene expression, amplifying molecular and neurodevelopmental disturbances.

(2) Synaptic Dysfunction and Neural Circuit Imbalance

Dysfunction in synaptic proteins and adhesion molecules leads to disrupted excitatory/inhibitory (E/I) balance in cortical and subcortical networks. Altered glutamatergic and GABAergic signaling, including NMDA receptor hypofunction and impaired inhibitory neurotransmission, are consistently observed. These disruptions impair synaptic plasticity and long-range connectivity, which underlie the social and cognitive deficits characteristic of ASD.

(3) Dysregulated Signal Transduction Pathways

Several intracellular pathways are abnormally regulated in ASD, notably the mTOR, PI3K/AKT, MAPK, and Wnt/β-catenin pathways. Hyperactivation of these signaling cascades results in excessive protein synthesis, impaired autophagy, and defective synaptic pruning. For example, hyperactivation of the mTOR pathway is frequently reported in both syndromic and idiopathic ASD, contributing to aberrant neuronal growth and reduced neural circuit plasticity.

(4) Immune and Neuroinflammatory Responses

Immune dysregulation is increasingly recognized as a key driver of ASD pathogenesis. Elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α) and activated microglia and astrocytes have been found in postmortem brain tissues and animal models. Maternal immune activation during gestation and gut microbiota dysbiosis further amplify neuroinflammation, disrupting synaptic homeostasis and contributing to altered neural development.

(5) Neuroanatomical and Connectivity Abnormalities

Neuroimaging and neuropathological studies consistently report structural and functional brain alterations, including cortical thickening, hippocampal and amygdalar volume changes, and altered white matter integrity. These anatomical abnormalities, combined with atypical connectivity between key social and cognitive networks, correlate strongly with behavioral phenotypes observed in individuals with ASD.

The pathogenesis of ASD is multidimensional, involving a cascade of genetic predisposition, molecular signaling dysregulation, synaptic dysfunction, and immune-neuroinflammatory processes. These converging mechanisms disrupt neural plasticity and brain network connectivity, resulting in the heterogeneous clinical manifestations of the disorder.

With these mechanism-relevant pathological nodes in mind, the following sections focus on how nanomaterials are being designed to intervene at these specific biological targets.

Nanomaterial-mediated genetic and epigenetic modulation for ASD treatment

Recent evidence indicates that serum-derived exosomes can act as “blood–brain messengers,” delivering microRNAs into the central nervous system, where they remodel gene expression and synaptic function in the medial prefrontal cortex (mPFC) and thereby influence core behavioral features of ASD. To test this hypothesis and define the mechanism, investigators established an exosome-induced ASD-like mouse model and identified the miR-29b-3p/insulin-like growth factor-1 (IGF-1) axis as a key pathway. Cheng et al. [187] reported a serum exosome–based nano-delivery system composed of lipid bilayer nanovesicles carrying miR-29b-3p to probe and intervene in ASD-related pathology. After tail-vein injection of exosomes isolated from valproic-acid (VPA) model rats, the vesicles entered the circulation, reached the brain, and crossed the blood–brain barrier by endothelial transcytosis; 20 h later, fluorescent signals were detected in the mPFC, indicating delivery. In the mPFC, exosomal miR-29b-3p bound the 3’-UTR of IGF-1 and suppressed its expression, which in turn downregulated gene networks linked to excitatory synaptic transmission, myelination, and neural connectivity, producing social deficits and repetitive behaviors. Blocking miR-29b-3p or supplementing IGF-1 locally in the mPFC restored IGF-1 levels, corrected transcriptional abnormalities and circuit imbalance, and improved ASD-like behaviors, including performance in the three-chamber social and social-novelty tests, achieving phenotypic reversal. Optogenetic activation of mPFC excitatory neurons yielded similar rescue effects, supporting the mPFC excitatory circuit as a critical effector site. In human-to-mouse translation, serum exosomes from individuals with ASD showed elevated miR-29b-3p; due to limited yield, these human exosomes were injected directly into the mouse mPFC, where they reproduced social deficits and repetitive behaviors and reduced local IGF-1 expression, aligning with the pathway defined in the peripheral-delivery model. These data position the exosome–miR-29b-3p/IGF-1 axis as a central molecular route in ASD. Using exosomes as nano-carriers to modulate this axis enables coordinated intervention from the genetic/epigenetic level to neural circuits and behavior, offering a translational strategy for ASD therapy.

Nanomaterial-mediated restoration of synaptic function and circuit balance in ASD

Core behavioral abnormalities in ASD are closely linked to excitation–inhibition imbalance and impaired synaptic plasticity within key circuits such as the prefrontal cortex–hippocampus pathway. Astrocytes are central to circuit stability because they support synaptic activity through the astrocyte–neuron lactate shuttle. When redox and metabolic homeostasis are disturbed, synaptic transmission declines and network imbalance is amplified. Thus, interventions that reinforce astrocytic metabolic support and restore the redox milieu may stabilize synapses from the bottom up, correct circuit dysfunction, and translate into improvements in social deficits and repetitive behaviors. Wu et al. [188] developed brain-targeted, H₂S-donor cross-linked nanomicelles, mannose-PEG600-lipoic acid (Man-LA), assembled from “mannose–PEG600” and lipoic acid (LA). The amphiphiles first self-assemble into micelles and are then cross-linked via disulfide bonds to increase stability and blood circulation time, aiming to improve ASD-related behavioral and neuropathological outcomes. Man-LA achieves active brain delivery through mannose recognition of GLUT1 expressed on brain endothelium and astrocytes. After entering the brain, Man-LA undergoes disulfide reduction in the glutathione-rich microenvironment and releases H₂S in a controlled manner. Released H₂S interacts with astrocytic Aldh3b1 and increases its expression, thereby promoting aerobic glycolysis and lactate production. At the cortical level, key glycolytic enzymes (e.g., HK isoforms, PKM2, LDHA) are upregulated, and cortical lactate and H₂S levels rise, consistent with enhanced astrocytic metabolic flux. Inhibition studies show that suppressing Aldh3b1 markedly weakens Man-LA’s ability to boost astrocytic glycolysis and lactate output, while H₂S release remains unchanged, supporting a functional sequence of “H₂S → Aldh3b1 → glycolysis/lactate”. Behaviorally and histologically, Man-LA reduces injury to hippocampal pyramidal neurons and significantly improves ASD-like phenotypes in marble-burying, self-grooming, open-field, and three-chamber social tests, outperforming non-targeted control micelles. These findings indicate that GLUT1-mediated brain delivery and glutathione-triggered H₂S release reinforce astrocyte glycolysis and lactate shuttling while maintaining redox balance. This support of synaptic transmission and plasticity stabilizes dysfunctional circuits and ultimately leads to system-level improvements in ASD-related behaviors.

Nanomaterial-mediated normalization of dysregulated signal transduction in ASD

Core behavioral features of ASD are closely linked to impaired synaptic plasticity and circuit-level imbalance. Targeted delivery within the brain that can reduce oxidative stress, restore mitochondrial function, and restart autophagy flux may stabilize neuronal homeostasis and synaptic transmission from the bottom up, leading to behavioral benefits. Feng et al. [189] reported a biomimetic nanomaterial, SCM@RAPA, composed of red-blood-cell membrane vesicles (CM) bearing DSPE-PEG-SS31 on the surface and loading rapamycin (RAPA), for ASD intervention. The cell-membrane camouflage reduces phagocytic clearance and prolongs circulation, while SS31, a mitochondria-targeting peptide, promotes interaction with brain microvascular endothelium and neural cells, thereby enhancing BBB transport and brain accumulation. Once in the brain, RAPA forms a complex with FKBP12 at the lysosomal surface and specifically inhibits mTORC1, which releases the brake on ULK1 and stabilizes the Beclin-1–VPS34 (PI3K-III) complex to drive phagophore nucleation and elongation. ATG7/ATG3 then mediate LC3-I lipidation to LC3-II and anchor LC3-II on nascent autophagic membranes, yielding the readouts LC3-II↑, Beclin-1↑, and p62↓ that indicate restoration of autophagy flux. Selective removal of damaged mitochondria follows, lowering ROS and stabilizing the mitochondrial membrane potential (ΔΨm). As the energetic and oxidative burden falls, synaptic transmission and plasticity recover. Single-cell transcriptomics and pathway analyses show upregulation of neuronal mitochondrial genes, suppression of excessive glutamatergic/GABAergic activity, and a shift of mitochondrial and synapse-related pathways toward a more normal pattern. After intravenous injection, in vivo imaging detected brain fluorescence at 2 h with a peak around 4 h, indicating rapid entry and enrichment, with pharmacodynamic effects in the hippocampus and other regions. Behaviorally and histologically, SCM@RAPA significantly improves social interaction, reduces hyperactivity/anxiety-related and repetitive behaviors in the three-chamber social test, open-field test, Y-maze, and self-grooming paradigms, and mitigates injury of hippocampal pyramidal neurons; overall efficacy exceeds that of non-targeted control carriers. These findings indicate that RBC-membrane camouflage and SS31-mediated brain delivery, combined with mTORC1 inhibition, restored autophagy flux, and mitochondrial homeostasis, stabilize abnormal activity at synaptic and circuit levels and translate into system-wide improvements in ASD-related behaviors.

Nanomaterial-mediated modulation of neuroinflammation and immune imbalance in ASD

One of the core pathological features of ASD is the excessive activation of neuroinflammation, particularly the abnormal hyperactivity of microglia and astrocytes. This dysregulation is often accompanied by oxidative stress, immune imbalance, and impaired synaptic function, ultimately leading to network dysfunction and behavioral abnormalities, including deficits in social interaction, cognitive impairments, and repetitive behaviors. In recent years, advances in nanotechnology—especially nanomaterials with multi-enzyme mimicking and immunomodulatory properties—have provided new strategies for the precise intervention of ASD.

Chen et al. [190] developed calcium hexacyanoferrate (III) nanocatalysts (CaH NCs), a nanomaterial constructed from a calcium hexacyanoferrate (III) lattice structure. Following stereotactic administration into the brain, CaH NCs achieve high accumulation in brain regions closely associated with ASD pathology, such as the hippocampus and prefrontal cortex. The mixed-valence Fe(III)–C≡N–Fe(II) lattice, combined with the reversible Fe²⁺/Fe³⁺ cycling and electron channels formed by the –C≡N– bridges, confers CaH NCs with multi-enzyme-like activities, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and peroxidase (POD). These catalytic properties enable rapid clearance of reactive oxygen species (ROS) such as O₂^−·, H₂O₂, and ·OH, effectively mitigating oxidative stress, stabilizing mitochondrial membrane potential (ΔΨm), and maintaining neuronal energy homeostasis. As oxidative pressure is alleviated, CaH NCs further suppress IKK–IκB–NF-κB and p38/JNK-MAPK signaling pathways, leading to the downregulation of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and upregulation of the anti-inflammatory cytokine IL-10, thereby reducing neuroinflammation. Concurrently, CaH NCs upregulate anti-apoptotic genes such as Bcl2l10, increase the Bcl-2/Bax ratio, and decrease cleaved caspase-3 levels, reducing mitochondria-mediated neuronal apoptosis. At the synaptic and circuit levels, CaH NCs restore synaptic energy supply and receptor dynamics, promote synaptic plasticity, and stabilize network activity by reducing abnormal synchronization. Behaviorally, valproic acid (VPA)-induced ASD model rats treated with CaH NCs exhibited enhanced social interaction, improved spatial and working memory, reduced anxiety-like behaviors, and decreased repetitive behaviors. Notably, CaH NCs also demonstrated preventive potential when applied during early developmental stages, mitigating neurodevelopmental abnormalities.

In contrast, Prussian blue nanoparticles (PB NPs) represent an earlier line of research. PB NPs are composed of an inorganic Prussian blue lattice and redox-active iron centers [191]. After stereotactic administration into the hippocampus, PB NPs exhibit localized accumulation in the targeted brain region. Their reversible Fe²⁺/Fe³⁺ cycling and electron channel network similarly endow PB NPs with SOD-, CAT-, GPx-, and POD-like activities, enabling efficient ROS scavenging, reduction of oxidative stress, and stabilization of mitochondrial membrane potential. Mechanistic studies further demonstrated that PB NPs attenuate NF-κB and p38/JNK-MAPK pathway activation, leading to reduced expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased expression of IL-10, thereby suppressing glial overactivation and promoting a shift of the neuroinflammatory environment toward resolution and repair. Additionally, PB NPs upregulate anti-apoptotic gene expression, elevate the mitochondrial apoptotic threshold, and protect neuronal integrity while maintaining energy supply and receptor turnover necessary for synaptic transmission. Behaviorally, PB NPs significantly improved social deficits, cognitive impairments, anxiety-like behaviors, and stereotyped behaviors in VPA-induced ASD model rats.

Comparative synthesis and translational implications of nanomaterial-based strategies for ASD

The current nanomaterial-based strategies for ASD span genetic and epigenetic modulation, restoration of synaptic and circuit balance, normalization of dysregulated intracellular signaling, and suppression of neuroinflammation or oxidative stress. This diversity reflects the multifactorial biology of ASD and suggests that nanomedicine may be particularly valuable in this field because it can be adapted to intervene at multiple mechanistic levels rather than relying on a single symptomatic pathway.

Among these strategies, redox-regulating and anti-inflammatory nanoplatforms have shown especially consistent preclinical benefits, likely because oxidative stress, mitochondrial dysfunction, and immune imbalance represent convergent downstream abnormalities across distinct ASD subtypes. By contrast, genetically and epigenetically oriented approaches may offer higher mechanistic precision, but their translation is more challenging due to disease heterogeneity, developmental timing, and concerns regarding durable safety in the immature or developing brain. Similarly, nanomaterials designed to modulate synaptic function and intracellular signaling are conceptually compelling, yet they require stronger validation across diverse ASD models and behavioral domains.

Overall, the ASD literature suggests that the greatest opportunity for nanomedicine lies in developing stratified, mechanism-informed platforms that can match intervention strategy to biological subtype. Future studies should therefore prioritize developmental-stage specificity, long-term neurodevelopmental safety, subtype-relevant outcome measures, and stronger integration between molecular pathology and nanoplatform design.

Comparative perspectives on nanomaterials for psychiatric disorders

Compared with neurological disorders, nanomaterial-based interventions for psychiatric disorders remain at an earlier stage of development, with fewer studies, less mechanistic stratification, and more limited validation in translationally relevant models. Across depression, schizophrenia, insomnia, and ASD, current applications are mainly concentrated in brain-targeted delivery, redox modulation, controlled release, and regulation of neuroinflammation or neurotransmission [192]. These strategies have generated encouraging preclinical results, particularly in improving bioavailability, reducing peripheral adverse effects, and enhancing therapeutic retention within the central nervous system.

However, the comparative review of these psychiatric sections also reveals a shared limitation: disease-specific molecular targeting remains relatively underdeveloped when compared with the more mechanistically differentiated nanomedicine literature in AD or PD. In many cases, nanomaterials are used primarily to optimize delivery efficiency rather than to engage the biological heterogeneity of each psychiatric disorder in a precise and stratified manner. Moreover, the translational evidence base is still restricted by relatively small study numbers, simplified animal models, limited long-term biosafety assessment, and insufficient evaluation of clinically meaningful behavioral or cognitive endpoints[193].

Therefore, psychiatric disorders represent both the most underrepresented area in the current bibliometric landscape and one of the most promising directions for future expansion. The major opportunity in psychiatric nanomedicine lies not only in improving BBB penetration or formulation performance, but also in identifying disorder-relevant biological targets that can support mechanism-driven nanoplatform design. Future progress in this field will depend on stronger integration among disease biology, nanomaterial engineering, and translational evaluation frameworks.

To provide an original comparative synthesis beyond the reproduced disease-specific figures, Table 15 summarizes the major nanomaterial-based therapeutic strategies across neurological and psychiatric disorders, emphasizing their dominant pathological targets, comparative strengths, and key translational barriers. This cross-disorder comparison highlights that the field is currently most mature in AD and PD, whereas psychiatric nanomedicine remains comparatively underdeveloped despite clear emerging potential.

Table 15.

Comparative overview of representative nanomaterial-based strategies for neurological and psychiatric disorders: pathological targets, strengths, and translational barriers

Disorder	Major pathological targets most relevant to nanotherapy	Representative nanomaterial strategy categories	Principal strengths	Main translational barriers	Relative research maturity
Parkinson’s disease (PD)	SNCA dysregulation, α-syn aggregation, mitochondrial dysfunction, neuroinflammation, impaired neuronal differentiation	Gene-regulatory nanocarriers, aggregation-inhibiting nanoplatforms, mitochondria-targeted nanoparticles, anti-inflammatory nanomedicines, differentiation-promoting systems	Strong mechanistic diversity; multiple upstream and downstream intervention nodes; high conceptual precision	Off-target genetic effects, delivery complexity, limited long-term safety data, scale-up and reproducibility issues	High
Alzheimer’s disease (AD)	Aβ pathology, tau aggregation, oxidative stress, abnormal gene expression, neuronal loss	Aβ-targeting nanoparticles, tau-directed systems, redox-regulating nanomedicines, gene-modulating carriers, NSC-related nanoplatforms	Broad therapeutic coverage; strong disease relevance; potential for multi-target intervention	Multifactorial disease complexity, uncertain long-term efficacy, limited chronic translational validation	High
Huntington’s disease (HD)	Mutant HTT expression, impaired autophagy/proteasomal degradation, mitochondrial injury	siRNA/gene-silencing carriers, autophagy-activating nanomaterials	Clear monogenic target; strong rationale for precision intervention	Limited breadth of validated platforms, delivery durability, safety of sustained gene-related intervention	Moderate
Ischemic stroke (IS)	Thrombotic occlusion, reperfusion injury, oxidative stress, inflammation	Thrombolytic nanocarriers, antioxidant nanoparticles, anti-inflammatory nanoplatforms	High clinical urgency; strong relevance for targeted and time-sensitive delivery	Narrow therapeutic window, biodistribution constraints, clinical timing and safety challenges	Moderate to high
Epilepsy	Excitation–inhibition imbalance, GABA/glutamate dysregulation, circuit hyperexcitability, neuroinflammation	Neurotransmission-modulating nanocarriers, circuit-targeted systems, anti-inflammatory platforms	Useful for improving brain delivery and reducing systemic exposure; mechanistically linked to network dysfunction	Limited circuit-level validation, chronic safety concerns, uncertain long-term seizure control benefits	Moderate
Depression	Neurotransmitter imbalance, oxidative stress, neuroinflammation, HPA-axis dysfunction	Antidepressant nanocarriers, redox-modulating systems, anti-inflammatory nanoplatforms, brain-targeted delivery systems	Good translational practicality; often based on clinically familiar drugs; improved bioavailability	Disease heterogeneity, limited mechanism-driven targeting, overreliance on simplified rodent models	Moderate to low
Schizophrenia	Epigenetic dysregulation, dopamine dysfunction, synaptic impairment, neuroinflammation	Epigenome-editing nanoplatforms, dopamine-regulating nanocarriers, intranasal delivery systems	Potential for precision targeting and improved CNS delivery; may reduce peripheral adverse effects	Mechanistically narrow evidence base, limited focus on cognitive/negative symptoms, long-term CNS safety uncertainty	Low
Insomnia	GABA/5-HT imbalance, HPA-axis overactivation, neuroinflammation, hyperarousal	Controlled-release sleep-promoting nanocarriers, GABA-regulating formulations, 5-HT-related delivery systems	Relatively straightforward formulation goals; potential for improved pharmacokinetics and sustained efficacy	Symptom-oriented rather than mechanism-deep; sparse evidence; limited long-term evaluation	Low
Autism spectrum disorder (ASD)	Genetic/epigenetic dysregulation, synaptic imbalance, abnormal signaling pathways, oxidative stress, neuroinflammation	Genetic and epigenetic nanoplatforms, synapse-regulating systems, signaling-pathway-targeted nanomedicines, antioxidant/anti-inflammatory nanoparticles	Strong fit for multi-level intervention; adaptable to heterogeneous biology	Developmental safety concerns, subtype heterogeneity, limited long-term neurodevelopmental validation	Moderate

Conclusion and outlook

The bibliometric findings of this study indicate that research on nanomaterials for neurological and psychiatric disorders has entered a sustained growth phase, with a marked acceleration in publication output after the mid-2010s. At the same time, the literature remains heavily skewed toward neurological disorders, whereas psychiatric applications account for a much smaller share of the field, identifying a clear underexplored direction for future work. Keyword burst and thematic analyses further suggest that the field is shifting from material synthesis and proof-of-concept studies toward disease-oriented design, targeted therapy, nasal delivery, and cognitive-function-related applications [194]. However, this growing sophistication at the preclinical level has not yet been matched by equivalent progress in clinical translation, largely because of unresolved issues in long-term safety, immune compatibility, reproducibility, and manufacturing scalability.

Therefore, the added value of the present review is not only to summarize representative nanoplatforms across disease mechanisms, but also to show—through bibliometric evidence—that future progress will likely depend on two priorities: first, rebalancing the field by strengthening psychiatric nanomedicine research; and second, advancing from efficacy-driven design toward standardized, translationally oriented evaluation frameworks.

(1) Design and Synthesis of Nanomaterials for Neurological and Psychiatric Disease Therapy

Although various nanomaterials have demonstrated therapeutic potential, the current methods for their design and synthesis often rely on empirical approaches, which may no longer suffice as the complexity of applications increases. Transitioning from empirical methods to rational design, based on theoretical models and computational tools, is crucial for advancing nanomaterial-based therapies. Integrating technologies such as big data analytics, machine learning, and artificial intelligence into nanomaterial research could facilitate the development of nanomaterials with optimized therapeutic properties. The design of nanomaterials for targeted delivery and overcoming biological barriers, such as the blood–brain barrier, is vital for enhancing their clinical efficacy.

(2) Precise Targeting and Mechanistic Understanding

The therapeutic effects of nanomaterials are largely determined by their ability to target specific disease mechanisms. However, the interaction between nanomaterials and biological systems is not fully understood, and more research is needed to elucidate the mechanisms behind their action. Understanding the factors that influence the activity of nanomaterials, such as size, surface charge, and functionalization, is critical for optimizing their performance. Advanced experimental and computational techniques, including spectroscopy, microscopy, and molecular simulations, should be employed to study these interactions at the atomic and molecular levels. This knowledge will guide the development of more efficient and targeted therapies [195, 196].

(3) Improvement of Nanomaterial Specificity and Delivery Systems

One of the main challenges in nanomaterial-based therapies is the general lack of specificity in targeting disease tissues. Unlike natural enzymes, which exhibit high specificity, nanomaterials often interact with a broad range of substrates. To improve the specificity of nanomaterials for treating neurological and psychiatric disorders, approaches such as surface modification, molecular imprinting, and structural engineering are promising strategies. Additionally, advances in targeted delivery mechanisms, such as receptor-mediated targeting and nanocarrier systems, will improve the precision of nanomaterial-based therapies [197].

(4) Translational Challenges and Clinical Application

Despite the promising results from preclinical studies, the translation of nanomaterials from laboratory research to clinical practice remains a significant challenge. To move from research to real-world applications, it is essential to address issues such as scalability, reproducibility, and regulatory approval. Ensuring the safety, efficacy, and stability of nanomaterials is crucial for their acceptance in clinical settings. Additionally, large-scale manufacturing processes need to be developed to produce nanomaterials with consistent quality and performance. Collaboration between researchers, clinicians, and regulatory bodies will be essential to overcome these barriers and bring nanomaterial-based therapies into clinical use.

(5) Biosafety and Ethical Considerations

The biosafety of nanomaterials, particularly in the context of long-term exposure and systemic distribution, remains a major concern. A thorough evaluation of their biocompatibility, potential toxicity, and environmental impact is necessary to ensure that these materials are safe for human use. In addition to further developing functional nanomaterials with improved safety profiles, regulatory standards must be established to evaluate the safety of these materials in biomedical applications. Ethical considerations regarding the use of nanomaterials in human therapy also need to be addressed, ensuring that their development benefits society while minimizing risks.

Future perspectives

Building on the bibliometric and comparative findings of this review, the future of nanomaterial-based therapies for neurological and psychiatric disorders is highly promising, but its progress will depend on whether the field can move from proof-of-concept efficacy toward mechanism-informed, clinically translatable design. However, several key challenges need to be addressed, including improving the specificity, safety, and scalability of nanomaterials. Future research should focus on optimizing the design of nanomaterials for targeted drug delivery, enhancing their stability, and understanding the underlying mechanisms that govern their interactions with biological systems. The interdisciplinary collaboration between material scientists, biologists, clinicians, and regulatory agencies will be crucial in overcoming the hurdles that currently limit the clinical application of nanomaterials. By advancing these technologies, nanomaterials could play a pivotal role in the next generation of therapies for neurological and psychiatric disorders, offering hope for more effective treatments with fewer side effects [198].

Author contributions

M.L.: writing-original draft, formal analysis; F.Z.: study concept or design, writing-original draft, resources, supervision; Y.W.: writing-review&editing, funding acquisition; Y.L. and J.B.: writing-review&editing, visualization. All authors read and approved the final manuscript.

Funding

This work was supported by Sichuan Province Natural Science Foundation (2026NSFSC1634), Guizhou Provincial Health Commission (gzwkj2026-133), The Health Commission of Sichuan Province Medical Science and Technology Program (24QNMP019), Traditional Chinese Medicine Basic Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine (25MSZX259).

Data availability

No datasets were generated or analysed during the current study.

Declarations

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Competing interests

The authors declare no competing interests.