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. 2023 Jun 27;6(7):2614–2621. doi: 10.1021/acsabm.3c00254

Recent Advances in Nanotherapeutics for Neurological Disorders

Arti Vashist †,‡,*, Pandiaraj Manickam §,%, Andrea D Raymond †,‡, Adriana Yndart Arias †,‡, Nagesh Kolishetti †,‡, Atul Vashist ∥, Emanuel Arias †,‡, Madhavan Nair †,‡,*
PMCID: PMC10354745  PMID: 37368486

Abstract

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Neurological disorders remain a significant health and economic burden worldwide. Addressing the challenges imposed by existing drugs, associated side- effects, and immune responses in neurodegenerative diseases is essential for developing better therapies. The immune activation in a diseased state has complex treatment protocols and results in hurdles for clinical translation. There is an immense need for the development of multifunctional nanotherapeutics with various properties to address the different limitations and immune interactions exhibited by the existing therapeutics. Nanotechnology has proven its potential to improve therapeutic delivery and enhance efficacy. Promising advancements have been made in developing nanotherapies that can be combined with CRISPR/Cas9 or siRNA for a targeted approach with unique potential for clinical translation. Engineering natural exosomes derived from mesenchymal stem cells (MSCs), dendritic cells (DCs), or macrophages to both deliver therapeutics and modulate the immune responses to tumors or in neurodegenerative disease (ND) can allow for targeted personalized therapeutic approaches. In the present review, we summarize and overview the recent advances in nanotherapeutics in addressing the existing treatment limitations and neuroimmune interactions for developing ND therapies and provide insights into the upcoming advancements in nanotechnology-based nanocarriers.

Keywords: Nanomaterials, Nanotechnology, Nanotherapeutics, Neurological disorders, Immune interactions

1. Introduction

The central nervous system (CNS) is exposed to several diseases and represents one of the human body’s complex systems. The global burden of disease (GBD) study evaluates the burden of neurological disorders concerning mortality, frequency, prevalence, years of life lost, and disability-adjusted life years (DALYs). Treatment for various neurological diseases has been challenging due to the complexity of the brain. A GBD study in 2019 suggested that DALYs of neurological disorders such as stroke, Alzheimer’s Disease (AD), Parkinson’s Disease (PD), brain and CNS cancers, and multiple sclerosis have increased worldwide.1,2 Neurodegenerative diseases (NDs) are primarily caused when the nerve cells in the brain lose function with time and eventually die. There is no cure for these diseases; however, there are continuous efforts to invent novel therapies to treat NDs. The leading cause of these diseases is related to genes present in individuals and the associated environment.

Neuroimmune interactions have gained much attention in identifying the multiple risks associated with various genes essential to the immune system. In a disease state, the hallmarks of immune activation play an important role in elucidating the signaling pathways and cellular markers to improve the diagnosis and therapeutics for NDs.3 Various reports and studies have shown a substantial increase in pro-inflammatory immune responses in NDs. Pro-inflammatory cytokines like IL-1,4,5 TNF-α,6,7 IL-12,8 and IL-69,10 increase in animal models and patient samples of AD. Studies suggest that lowering these pathways can result in improved cognition and reduced levels of Aβ plaque formation in AD. It is important to note that microglia and astrocytes are the major cell types responsible for phagocytosis and cytokine secretion. Astrocytes play an important role in blood−brain barrier (BBB) maintenance and glial scar formation. Therapies targeting the microglia-associated pathways can be efficient. Researchers worldwide are developing novel medicines to overcome hurdles such as formidable BBB transmigration and neuroinflammation and address the immune alteration in the brain.

The therapeutics invented for CNS diseases have limited clinical efficiency due to poor drug delivery systems. The continuous consumption of drugs, the side-effects associated with it, and factors like aging and aging-related comorbidities have made the treatment very challenging. The most common and prominent challenge includes the BBB, where the delivery of drugs is tedious. In this regard, nanotechnology has gained much attention. The nanosized and multifunctional characteristics enable nanomaterial interactions at the molecular level and deliver the therapeutics at the target diseased site. There is an immense need to develop a nanocarrier tagged to selective ligands that can bind to target tissues/cells, increase efficacy, and reduce toxicity of a drug embedded in the nanocarrier. Aptamer-based targeting has also shown potential in the treatment of brain diseases.11 The nanomaterials can be functionalized to achieve sustained and controlled drug release and modified to cross solid physiological barriers. Diverse nanocarriers such as liposomes,12 dendrimers,13 polymeric nanoparticles,14 inorganic nanoparticles,15 exosomes,16 and micro/nanogels17 have shown great potential in delivering various drugs for treating neurological disorders. In this article, we will highlight the critical nanocarriers, their characteristics, and the advancements in their development for neurological disorders.

2. Liposomes

Liposomes are well-established, clinically proven nanocarriers (Table 1) that have been explored for several years.18 These nanocarriers have shown significant therapeutic potential to treat various neurological disorders. These are spherical-shaped vesicles with one or more phospholipid layers resembling the cell membrane structure. These nanocarriers can incorporate both hydrophilic and hydrophobic drugs. Liposomes have shown promising results as the phospholipid bilayer facilitates transport across the BBB. Liposomes are well-known for their biocompatibility; lipid origins can safely circulate to the peripheral organs and can perform noninvasive delivery. Liposomes are being modified with PEG, specific ligands, and peptides such as rabies virus peptides (RVG) which are very specific to target brain diseases like AD, PD, and carcinomas.18,19 A recent study by dos Santos Rodrigues et al.19 developed liposomes by conjugating transferrin and RVG peptide to the surface of liposomes. These liposomes showed a better ability to transfect cells than naked liposomes without any surface modifications. Thus, liposomes could be used for efficient gene delivery by using brain-targeting ligands.

Table 1. Liposomal Formulations under Various Phases of Clinical Trials.

formulation drug target phase reference
Liposome cytarabine solid tumor neoplastic meningitis I NCT00854867
    brain and central nervous system tumors leukemia lymphoma I NCT00003073
  doxorubicin brain metastases from breast cancer II NCT00465673
    primary brain lymphoma II NCT01848652
    brain tumor, bone cancer, kidney tumor, childhood liver cancer I NCT00019630
  2B3-101(glutathione PEGylated liposomal doxorubicin hydrochloride brain metases, lung cancer, breast cancer, melanoma, malignant glioma I/II NCT01386580
  methotrexate, cytarabine central nervous system metastases, leptomeningeal metastases II NCT00992602
  Marqibo sarcoma, neuroblastoma Wilms tumor, leukemia lymphoma, brain tumors I NCT01222780
  ITV DepoCyt and temozoiomide gliobiastoma multiforme glioma, astrocytoma brain tumor I/II NCT01044968
  irinotecan diffuse intrinsic pontine glioma I NCT03086616
    solid tumors ER/PR positive breast cancer, triple negative breast cancer metastatic breast cancer with active brain metastasis I  
  rhenium glioma I/II NCT01906385
  talineuren Parkinson disease I NCT04976127
  total tumor mRNA adult glioblastoma I NCT04573140
  bupivacaine craniofacial pain, migraine, cluster headache, trigeminal automatic cephalgia, sphenopalatine gangilion neuralga, paroxysmal hemicrania II NCT04930887
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Reproduced with permission from ref (18) under the terms of a CC BY-NC-ND license. Published 2022 Elsevier.

Liposomes have also been extensively explored for image-guided drug delivery. In one of the studies from our lab,20 we developed multifunctional magneto-plasmonic liposomes (MPLs) and loaded tenofovir disoproxil fumarate for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. These MPLs could transmigrate across an in vitro BBB model by magnetic targeting and enhance therapeutic efficacy against HIV infection in microglial cells. Figure 1 presents the structure of magneto-plasmonic liposomes and shows the bright, positive contrast in X-ray computed tomography (CT).20 The characteristic properties of liposomes and their structure allow them to have no or minimal immune system activation to act as an efficient drug delivery system.21

Figure 1.

Figure 1

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Hybrid magneto-plasmonic liposomes for multimodal image-guided and brain-targeted HIV treatment. Reproduced with permission from ref (20). Copyright 2018 Royal Society of Chemistry.

3. Dendrimers

Dendrimers are polymeric macromolecules having hyperbranched network architectures with tunable surface functionalities. Dendrimer structure consists of an interior core, branching polymeric layers known as dendrons, and a peripheral shell. Dendrimers act as nanocarriers for efficiently transporting biological molecules (antigens/antibodies/oligonucleotides) and drug molecules in a biological system. Dendrimers have been widely explored as a nanocarrier due to their advantages, such as biocompatibility, drug-loading capacity, surface functionalization ability, tunable solubility, and pH stability. The emergence of dendrimer-based formulations allows innovations in the field of nanomedicine, including diagnosis/imaging and therapeutics.

Engineered porous silicon nanoparticle conjugated antisense oligonucleotides as a targeted drug delivery system for the clinical treatment of glioblastoma have been attempted.22 Glioblastoma is an aggressive tumor that originates in the brain. In this case, porous silicon nanoparticle is acted as core and conjugation of oligonucleotide leads to the formation of well-organized dendrimer like structure. Treatment of glioblastoma is challenging due to the poor accumulation of drugs at the target region caused by the BBB. Luo et al.22 have combined the antisense oligonucleotide approach with nanocarrier technology for targeted drug delivery. The antisense oligonucleotides attack “downregulated in renal cell carcinoma” (DRR) protein responsible for glioblastoma invasion. The porous silicon nanoparticles were functionalized with undecylenic acid for immobilizing oligonucleotides through EDC/NHS chemistry. The controlled release of antisense oligonucleotides from the porous silicon nanoparticles was achieved through pH-dependent cargo release. The ability of the proposed antisense-loaded nanocarrier to penetrate the BBB network was demonstrated using a microfluidic-based BBB model and xenograft mouse models (Figure 2).22

Figure 2.

Figure 2

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Schematic representation of functionalizing porous silicon nanoparticles (pSiNPs) with undecylenic acid and immobilizing antisense oligonucleotides (AONs) on undecylenic acid functionalized silicon nanoparticles (A). Assembly of the microfluidic chip-based device for demonstrating BBB penetrating capability (B). Testing BBB penetration ability and biodistribution in glioblastoma xenograft mouse model (C). Reproduced with permissions from ref (22). Copyright 2023 American Chemical Society.

The size of the nanocarrier is essential for improving cancer-targeting efficiency and biodistribution. Liaw et al. have demonstrated the effect of nanocarrier size on brain tumor targeting efficiency and BBB penetrating capability.23 Poly(amidoamine) (PAMAM)-based dendrimers functionalized with hydroxyl groups have been investigated as delivery vesicles for targeted therapeutics to brain tumors. Generatation-4 (G4) dendrimers with particle size ∼4.3 nm and G-6 dendrimers with size ∼6.7 nm have been explored for targeted immunotherapeutics. The clinical utility of the nanocarriers was demonstrated in two different mouse models (9L and GL261). Findings indicate that the G6 dendrimer showed optimal tumor penetrating ability and renal clearance and better biodispersibility than the G4 dendrimer. Although both the G4 and G6 dendrimers showed high sensitivity in targeting the tumor cell, the G4 dendrimer exhibited a rapid clearance effect due to its small size leading to reduced bioavailability.23

A PAMAM dendrimer conjugated small-interfering RNA (siRNA) for targeted therapeutics in CNS disorders was explored. siRNA is a synthetic double-stranded RNA that acts as a gene silencer and reduces disease-related protein expression. siRNA molecules are unstable and prone to enzymatic degradation and protein binding. To mitigate the issues of dendrimers, conjugated siRNAs were prepared using glutathione cross-linkers.24 Conjugation with dendrimer allows precise cargo loading and improves the stability of siRNAs toward early degradation. The performance of the proposed model is also compared with commercial drug delivery systems (Figure 3).24 Nance et al. demonstrated that the density of the hydroxyl groups is vital for enhanced drug delivery by crossing impaired CNS barriers and target site accumulation.25 The intrinsic therapeutic outcomes of surface hydroxyl functionalized dendrimers for CNS targeted therapy were not observed with the anionic and cationic dendrimers, which do not possess a surface hydroxyl group. Based on this, researchers have synthesized PEG-based dendrimers with high surface hydroxyl group density and explored them as potential nanocarriers for CNS disorders.26

Figure 3.

Figure 3

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Dendrimer conjugated siRNA to target tumor-associated macrophage mouse model and penetration of the dendrimer–siRNA nanocarrier across the BBB. Reproduced with permissions from ref (24). Copyright 2022 American Chemical Society.

Dendrimers can also trigger undesirable immune responses, such as inflammation or autoimmunity, by activating immune cells, enhancing antigen presentation, and stimulating cytokine production. which can be harmful in some neurotherapeutic applications. For example, dendrimers have been shown to induce neuroinflammation and neurotoxicity in some experimental models, which may limit their utility for certain neurodegenerative diseases. Dendrimers can activate immune cells such as macrophages or dendritic cells, which can then produce cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), or TNF-α.27 These cytokines can promote neuroinflammation and neuroprotection, depending on their concentration, timing, and duration. Dendrimers can also modulate intracellular calcium levels, which can affect cytokine release from neuronal cells.

4. Magnetic Particles

Magnetic nanoparticles are one of the emerging nanomaterials for targeted therapeutics. The magnetic properties of the nanoparticles rely on superparamagnetic characteristics, which allow them to emerge as candidates in stimuli-responsive targeted therapeutics. Traditional drug delivery approaches are limited by providing the optimum concentration of drug doses at the target site. Magnetic particles functionalized with biological or chemical drug molecules can be actuated and controlled in the natural system through an external magnetic field. This makes them suitable for delivering drugs for CNS disorders where conventional approaches fail to penetrate the BBB. Magnetic nanoparticles have been investigated as potential therapeutics for a range of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, muscular dystrophy, NeuroAIDS, and brain tumors.28,29

Superparamagnetic iron oxide nanoparticles are one of the most extensively explored inorganic nanoparticle systems for targeted drug delivery. Magnetic particles can be synthesized in sizes ranging from 1 to 1000 nm. For targeted therapeutics, magnetic particles smaller than 200 nm are preferred.30 The low dispersibility of the iron oxide nanoparticles in hydrophilic solvents is a critical issue for cargo loading and delivery. In recent years, magnetic iron oxide nanoparticles functionalized with amino or carboxylic acid groups have shown improved dispersibility. Magnetic iron oxide nanoparticles coated with oligosaccharides were explored as a nanocarrier for targeting brain tumors. Magnetic particles with a size of less than 5 nm were synthesized and covalently conjugated with oligosaccharides, and the ability to penetrate the BBB was demonstrated in the orthotopic mouse model.31 The oligosaccharide-coated magnetic particles allowed the noninvasive imaging of cancer cells through magnetic resonance imaging for improved theranostics application (Figure 4). The ability of magnetic particles to deliver drugs and various therapeutic agents by penetrating BBB has also been explored in multiple mouse models.32

Figure 4.

Figure 4

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Schematic representation of immobilizing oligosaccharides onto magnetic particles and targeted therapeutic applications. Reproduced from ref (32) under Creative Commons CC-BY License. Published 2020 Elsevier.

Polymeric encapsulation of magnetic particles was also explored for enhancing the particle’s colloidal stability, which could result in practical BBB crossing ability. The protection from degradation of the drug by proteins and the bioavailability of the drug are also enhanced by polymeric coatings.33 Poly(lactic-co-glycolic acid) functionalized magnetic iron oxide nanoparticles (Fe3O4) were modified with carnosine and dexamethasone for targeted treatment of ischemic stroke. The ability of the modified magnetic particles was demonstrated in brain capillary endothelial cells.34 Magnetic actuation was also used to construct magnetic micro/nanorobots that mimic biological locomotion activities. Zhang et al. reported a neutrophil-based microrobot for delivering a cargo to glioma tumor cells in vivo.35 The applied external magnetic field drives the movement of particles to the brain suggesting transport across the BBB. Colloidal stability of magnetic particles is an essential criterion in developing an efficient drug delivery system to the brain. The superparamagnetic properties stabilize the magnetic particles without aggregation in aqueous media. The magnetic particles are also coated with ligands such as transferrin, lactoferrin, curcumin, and BBB penetrating peptides, allowing BBB penetration.36 The immune response of brain cells to magnetic nanoparticles can vary depending on the nanoparticle’s size, shape, surface chemistry, dosage, and route of administration.37 Particles with larger size are more readily recognized by the immune system, leading to a stronger response, while smaller particles may be able to evade detection. Additionally, the surface chemistry of the nanoparticles can influence their interaction with immune cells, with some coatings being more immunogenic than others. Magnetic nanoparticles with a positive surface charge may induce a stronger immune response than those with a neutral or negative surface charge. Several strategies are adopted to address the issues related to immune responses observed in brain drug delivery using magnetic nanoparticles. Mostly the coating of magnetic nanoparticles using a biocompatible polymer is preferred. Another intelligent approach to modify the surface of the particles is using poly(ethylene glycol) (PEG), which can form a coating outside the particles and inhibit the immune response.

5. Exosomes

Exosomes are extracellular vesicles secreted by most nucleated eukaryotic cells and prokaryotic cells and can serve as endogenous nanoparticles. Depending on the origin and functional status of the cell, the exosomes contain many constituents, which include proteins, DNA, RNA, metabolites, and lipids. Primarily, exosomes function in intercellular communication and can regulate T-cell mediated immune responses, autoimmunity, and inflammation.38 Exosomes are also associated with the pathology of neurodegenerative disorders such as PD, AD, and even prions. However, natural exosomes from mesenchymal stem cells (MSCs) retain the capacity promote neurite remodeling, immune modulation, migration, and homing. Recent reports demonstrated that engineered MSC-derived exosomes (MSC-exos) migrated to specific diseased regions of the brain in PD39 and AD40 disease models. DC-derived exosomes were shown to be immunomodulatory during stroke41 while macrophage-derived exosomes were neuroinflammatory.42

The inner core of the exosome contains biologically active molecules, and the outer layer consists of a phospholipid envelope. Exosomes come in various sizes ranging from 40 to 160 nm (average ∼100 nm) in diameter. Exosomes can be functionalized with drug molecules for targeted therapeutics as a nanosized natural carrier. This can be achieved by modulating them to deliver diverse therapeutic payloads.43 Interestingly, exosomes found in bodily fluids (e.g., blood, saliva, urine, breast milk, etc.) are biocompatible and nonimmunogenic and can easily pass through cellular barriers such as the blood–brain barrier. As a result, exosomes derived from cells in the CNS can be found in the peripheral blood and vice versa. This property makes exosomes a potential nanoparticle for drug delivery to the brain. Numerous ways have been reported to load a drug into the exosomes (Figure 5).

Figure 5.

Figure 5

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Classification of exosome drug loading methods. Reproduced from ref (44). Published 2023 by American Chemical Society under CC BY 4.0 license.

Exosome drug loading can be broadly categorized into two major types: (i) dynamic loading and (ii) passive methods. In active mode, the purified exosomes are used to load the cargo, and in the passive method, the drug molecule incubated cells are purified to get the drug-loaded exosomes.44

Exosomes are an integral communication medium between the brain and the periphery. They are secreted from neurons and brain endothelial cells, essential in the pathology and physiology of complex interconnected CNS networks.45 Due to their small size and endogenous properties, exosomes are suitable for brain drug delivery, requiring BBB penetration. Natural exosomes can pass through the BBB by interacting with receptors in the brain endothelial cells. Based on the interaction of exosomes with transferrin receptors, the exosomes have been explored for delivering neurotransmitters (dopamine) across the BBB for Parkinson disease therapy.46 Exosomes play a role in cell-to-cell communication and can modulate immune responses. For example, immune cells such as dendritic cells and macrophages release exosomes that can activate or suppress immune responses, depending on their cargo.47

6. Nanogels

Nanotechnology has come up with advancements in hydrogel technology by innovating smart nanogels, which have more advanced properties than bulk three-dimensional cross-linked hydrogels.48 Nanogels are the nanoparticle form of hydrogels in the range of 1–100 nm. Each nanocarrier has its characteristics and advantages over others. The nanocarriers discussed so far have limitations for preclinical applications, such as liposomes needing better stability and requiring rigorous storage conditions. Inorganic nanocarriers are still questioned for their toxicity and biodegradability, and polymer particles of poly(lactic acid-glycolic acid) copolymer (PLGA) are accompanied by drug burst release issues.49 Studies have shown that nanogels address these limitations to a great extent and have high biodegradability, high biocompatibility, high stability, and easy storage conditions.50 Studies show that nanogels intranasally administered show enhanced uptake of insulin in the brain.51,52Figure 6 displays a schematic for poly(N-vinylpyrrolidone)-based nanogels developed using e-beam irradiation for covalently binding the insulin and tested for brain delivery.52 The study demonstrated that nanogel, when intranasally delivered, showed no immunogenic response of the nasal mucosa. This study shows the potential of nanogels as therapeutic agents against some NDs.

Figure 6.

Figure 6

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Nose-to-brain delivery of insulin enhanced by a nanogel carrier. Reprinted from ref (52), Copyright 2018, with permission from Elsevier.

Chitosan-based nanogels, loaded with piperine when delivered intranasally, have shown improved cognitive function in vivo in mice studies.53 Olanzapine loaded in chitosan-based nanogels demonstrated good nasal drug absorption.54 Fascinating research developed a hydrogen bond-enhanced nanogel system (glycyrrhizic acid–zinc alginate nanogel, GA-NG) which exhibits antioxidant and anti-inflammatory properties. This nano-hydrogel showed selective brain distribution and accumulation. This nano-hydrogel system showed improved stability and used hydrogen bonding sites for active small molecules.55 These kinds of studies justify the potential of nanogels for sustained release carriers for PD and are capable of noninvasive drug administration. We have summarized in detail potential of nanogels for theranostics in a recently published article elsewhere.56

7. Prospects and Conclusions

The advancement in the development of nanotherapeutics for treating and diagnosing neurodegenerative diseases holds excellent potential for clinical translation. Nanotechnology has evolved in the last five years, developing nanocarriers that regulate inflammation and immune-related NDs. Current therapies for NDs and disease states have demanded the development of multifunctional nanocarriers with inherent anti-inflammatory, antibacterial, and antioxidant properties. RNAi has come up with treatments that are in preclinical trials by various companies and research groups. Several pathways can be suppressed using RNAi and it can block specific mRNA. Thus, nanotherapeutics for siRNA-based therapies give rise to new avenues for treating NDs. Nanogels have exclusive potential for noninvasive delivery and can come up with multifunctional smart nanocarriers and may emerge as therapies for NDs. Moreover, CRISPR/Cas9 gene editing utilizing nanocarriers also holds potential for direct treatment. It can target the specific genes in early onset AD and late-onset AD, the apolipoprotein E4 (APOE4) gene.

Natural exosome modulation of immune responses and the capacity to deliver drugs across the BBB makes these endogenous nanoparticles potential candidates for nanotherapeutics to treat neurodegenerative diseases (and cancers). Not only are exosomes biocompatible with the ability to easily cross the BBB, but they can be targeted to specific diseased regions of the brain. Natural exosomes from specific cell sources (MSCs, dendritic cells (DCs), and macrophages) represent a novel paradigm of personalized medicine for treatment of degenerative neurological disorders.

Acknowledgments

Madhavan Nair acknowledges the support from the National Institutes of Health (NIH), Grants DA042706, DA040537, DA037838, DA052271, and DA034547, and Florida Department of Health Grant 8AZ04. Pandiaraj Manickam acknowledges CSIR-CECRI Manuscript Communication Number: CECRI/PESVC/Pubs/2023-058.

Author Present Address

# Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, 201310, India

The authors declare no competing financial interest.

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