Nanotechnology-based targeted regulation of NLRP3 Inflammasome: therapeutic strategies and clinical application prospects in inflammatory diseases

ABSTRACT

The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.

GRAPHICAL ABSTRACT

1. Introduction

Inflammation is a complex and essential response of the body to external stimuli. It serves as a fundamental defense mechanism orchestrated by the immune system, playing a critical role in the recognition and elimination of harmful agents as well as in initiating the healing process (Germolec 2018; Chopra 2024). Depending on the severity and duration of symptoms, inflammation can be classified into two major forms: acute and chronic (Arulselvan 2016). When an acute inflammatory response triggered by pathogens fails to be resolved effectively, it may develop into chronic inflammation, resulting in long–term health impacts. This progression can manifest in multiple organ systems and cause tissue damage or the onset of various diseases (Wu et al. 2014; Chopra 2024). Chronic inflammation is a key contributor to the development and progression of numerous diseases, involving pathological processes such as immune dysregulation, cytokine storms, and oxidative stress (Hall 2021; Marketkar 2024). Inflammation–related diseases significantly impair patients' quality of life and impose a heavy burden on healthcare systems. In recent years, increasing evidence has revealed close associations between inflammation and various conditions such as aging and cancer (Mantovani et al. 2008; Singh 2024). These diseases affect multiple organs and systems, including the liver (Koyama and Brenner 2017), pancreas (Habtezion 2015), heart (Prabhu and Frangogiannis 2016), brain (Lee et al. 2023), lungs (Savin et al. 2022), kidneys (Neumann and Tiegs 2021), digestive tract (Harold 2022), and reproductive system (Saunders and Horne 2021).

Inflammasomes are cytosolic multiprotein complexes assembled by pattern recognition receptors (PRRs), which mediate innate immune defense and are closely associated with a wide range of diseases. They are primarily responsible for the regulation of interleukin-1β (IL-1β) and interleukin−18 (IL−18) secretion (Rathinam and Fitzgerald 2016). These potent pro–inflammatory cytokines play a crucial role in host defense against pathogens and in inflammatory responses triggered by danger signals (Zangiabadi and Abdul-Sater 2022). Among various identified inflammasomes involved in inflammatory processes, the NOD–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It plays a pivotal role in responding to pathogenic infections and danger signals. Aberrant activation of the NLRP3 inflammasome has been closely linked to a variety of human diseases, including inflammatory, autoimmune, and metabolic disorders (Zhang et al. 2021; Chen 2023). Therefore, modulating and intervening in the activation of the inflammasome is crucial for maintaining immune homeostasis and functionality, positioning the NLRP3 inflammasome as an ideal therapeutic target for inflammation–related diseases (Coll et al. 2022). Currently, research on small molecules and biologics targeting the NLRP3 inflammasome pathway has yielded promising outcomes. Blocking chronic inflammation through this approach has proven effective in treating multiple diseases (Blevins et al. 2022). However, the development of selective and effective NLRP3 inhibitors with favorable pharmacokinetic properties, particularly those capable of crossing the blood–brain barrier for central nervous system diseases, remains a significant challenge. Further research is needed to understand better the binding modes and mechanisms of action of compounds targeting this pathway.

In recent years, nanotechnology has rapidly advanced in the field of medicine, offering new avenues for the precise targeting of the NLRP3 inflammasome and enabling the precision treatment of inflammatory diseases. Owing to their nanoscale size, surface modifiability, biocompatibility, and favorable properties for targeted drug delivery and side effect reduction, nanomaterials exhibit numerous advantages in inflammation regulation and therapeutic delivery (Rosenblum et al. 2018; Chen et al. 2019). For example, certain NLRP3 inhibitors, such as colchicine, often suffer from strong adverse effects, poor solubility, and rapid metabolism (Tang 2023). Nanocarrier technologies can significantly enhance the stability and tissue penetration of these inhibitors while minimizing adverse effects, thereby improving therapeutic efficacy (Suk et al. 2016). Nanoparticles can respond precisely to external or internal stimuli, such as pH, reactive oxygen species (ROS), or biological targeting, allowing for site–specific, controlled drug release and precise delivery (Zhu 2017; Qin and Li 2020). Furthermore, nanoparticles themselves can exert anti–inflammatory effects by mechanisms such as antioxidant activity, modulation of lysosomal homeostasis, and inhibition of gasdermin D (GSDMD), thereby disrupting NLRP3 inflammasome activity (Zhu 2024). Moreover, functional surface modification of nanoparticles can enable them to effectively cross the blood–brain barrier (BBB), facilitating the targeted delivery of therapeutics to neurons and astrocytes in the brain, which provides new strategies for the treatment of neuroinflammatory disorders (Wang 2025).

Despite the tremendous potential of nanotechnology in inflammation therapy, the specific mechanisms and clinical translation of nanotechnology targeting the NLRP3 inflammasome remain under investigation. This review aims to explore in depth the mechanistic role of the NLRP3 inflammasome in inflammation–related diseases and to highlight its significance as a potential therapeutic target. It will further summarize the latest advances in nanotechnology for precise targeting of the NLRP3 inflammasome, detailing the various types of nanomaterials and their unique mechanisms of action. Additionally, the article will discuss the wide range of applications of nanotechnology in treating inflammation–related diseases such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, diabetes, and neurodegenerative diseases. Finally, it will analyze the current challenges and future research directions, including issues of nanomaterial safety, biocompatibility, and translational feasibility for clinical applications.

2. NLRP3 Inflammasome: structure, assembly, and activation

The NLRP3 inflammasome is a cytoplasmic multiprotein complex that responds to microbial infections, endogenous danger signals, and environmental stimuli. Upon assembly, the NLRP3 inflammasome activates caspase−1, leading to Gasdermin D (GSDMD)-dependent pyroptosis and promoting the release of IL-1β and IL−18, thereby contributing to innate immune defense and homeostasis maintenance (Huang et al. 2021). In this section, we briefly outline the structure, assembly, and activation pathways of the NLRP3 inflammasome, and analyze in detail its mechanism of action in inflammatory processes.

2.1. Structure and assembly

As illustrated in Figure 1, the NLRP3 inflammasome is composed of NLRP3, apoptosis–associated speck–like protein containing a CARD (ASC), and pro–caspase−1 (Chen et al. 2021; Fu and Wu 2023). NLRP3 is a pattern recognition receptor (PRR) belonging to the nucleotide–binding oligomerization domain (NOD)-like receptor (NLR) family (He et al. 2016). The C–terminus of NLRs contains leucine–rich repeats (LRRs), which recognize damage–associated molecular patterns (DAMPs) and pathogen–associated molecular patterns (PAMPs) (Figure 1a). The central nucleotide–binding domain (NACHT) is a key structural component, consisting of several subdomains (Figure 1a), including the fish–specific NACHT–associated domain (FISNA), nucleotide–binding domain (NBD), helical domain 1 (HD1), winged–helix domain (WHD), and helical domain 2 (HD2) (Dekker 2021). It functions as a deoxyribonucleoside triphosphate (dNTP) hydrolase and hydrolyzes ATP. The N-terminus of NLRP3 contains a pyrin domain (PYD), which is part of the death domain (DD) superfamily characterized by a six–helix bundle structure–a conserved protein motif involved in cell death processes such as apoptosis and pyroptosis (Bae and Park 2011). The PYD interacts with the PYD of ASC via homotypic PYD–PYD interactions to recruit ASC, which also contains a caspase recruitment domain (CARD) (Figure 1b). ASC, in turn, recruits pro–caspase−1 through CARD–CARD interactions to form and activate the NLRP3 inflammasome (Szabo and Csak 2012; Huang et al. 2021; Zhang et al. 2023). Pro–caspase−1 consists of a CARD domain and a catalytic domain (p20-p10), and upon activation, it is cleaved into the p20 and p10 subunits (Figure 1b). Activated NLRP3 undergoes oligomerization and recruits ASC through PYD homotypic binding. The NLRP3-ASC complex then recruits multiple pro–caspase−1 molecules via CARD interactions, ultimately forming the active NLRP3 inflammasome that modulates inflammatory responses and immune functions (Ma 2023). Once activated, caspase−1 cleaves downstream substrates such as pro–IL-1β, pro–IL−18, and GSDMD, resulting in the release of mature IL-1β, IL−18, and the GSDMD N-terminal fragment (GSDMD–NT), thereby inducing pyroptosis and inflammation (Wang and Hauenstein 2020) (Figure 1c).

Figure 1.

(a) NLRP3 domains. (b) The sensor–adapter–effector machinery of the NLRP3 inflammasome, depicting interaction of NLRP3 with ASC through their PYDs, and interaction of ASC with caspase−1 through their CARDs. (c) A molecular model of the NLRP3 inflammasome pathway, stepwise from upstream (❶) to downstream (❽). NLRP3 conformational change and the subsequent intracellular trafficking lead to the binding of NLRP3 to NEK7, which induces formation of an NLRP3 inflammasome disk and promotes NLRP3 PYD to form a filament. The NLRP3 PYD filament recruits ASC by nucleating the ASC PYD filament. The CARD of ASC also clusters and forms a filament. The ASC CARD filament recruits caspase−1 by nucleating the caspase−1 CARD filament. The caspase−1 caspase domain (p20/p10) dimerizes and autoprocesses, resulting in its activation. The active caspase−1 then cleaves pro–cytokines in the IL−1 family to generate mature cytokines. Caspase−1 also cleaves GSDMD to generate an active GSDMD N-terminal fragment for membrane pore formation that facilitates cytokine release and pyroptosis. Abbreviations: ASC, apoptosis–associated speck–like protein containing a caspase recruitment domain; CARD, C–terminal caspase recruitment domain; FISNA, fish–specific NACHT–associated domain; GSDMD, gasdermin D; HD1, helical domain 1; LRR, leucine–rich repeat; NBD, nucleotide–binding domain; NEK7, NIMA–related kinase 7; PYD, pyrin domain; WHD, winged helix domain (Fu and Wu 2023).

2.2. Activation and regulation of the NLRP3 inflammasome

The NLRP3 inflammasome is a critical component of the innate immune system. It is widely accepted that the activation of a canonical NLRP3 inflammasome requires two distinct steps: priming and activation (McKee and Coll 2020) (Figure 2). Full activation of the NLRP3 inflammasome involves the release of autoinhibition, NACHT oligomerization, ASC speck formation, caspase−1 recruitment and autoactivation, and the cleavage and maturation of IL-1β and other caspase−1 substrates (Swanson et al. 2019; Kelley et al. 2019; Liu et al. 2022; Ma 2023).

Figure 2.

Activation and effector functions of the NLRP3 inflammasome (Liu et al. 2022).

As depicted in Figure 2, the activation process begins with a ‘priming’ signal, typically triggered by PAMPs or DAMPs through Toll–like receptors (TLRs) or other PRRs. This step leads to the activation of nuclear factor-κB (NF-κB), which in turn upregulates the expression of NLRP3 and pro–IL-1β (Bauernfeind 2009; Kinoshita et al. 2015). Following priming, a second ‘activation’ signal is required, usually triggered by intracellular changes such as ionic flux (e.g. K⁺ efflux, Cl⁻ efflux, Na⁺ influx, and Ca²⁺ mobilization), mitochondrial dysfunction, reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA) release, lysosomal rupture, and Golgi disassembly–all of which are considered upstream signals that promote NLRP3 inflammasome assembly and activation (Huang et al. 2021; Ma 2023). These stimuli induce conformational changes in NLRP3, facilitating its interaction with ASC and the formation of the inflammasome complex. Once assembled, ASC recruits and activates caspase−1, which processes pro–IL-1β and pro–IL−18 into their mature forms, thereby initiating inflammation and pyroptosis (Wang and Hauenstein 2020). Although these pathways are commonly involved in NLRP3 activation, not all NLRP3 agonizts utilize the same upstream mechanisms, indicating variability in NLRP3 sensing and activation, which remains to be fully elucidated (Huang et al. 2021). Overall, the activation of the NLRP3 inflammasome is a complex process involving multiple cellular signals and molecular interactions, and it plays a key role in the pathogenesis of many inflammatory diseases.

Reactive oxygen species (ROS), particularly those derived from mitochondria (mtROS), play a crucial role in NLRP3 activation (Xu 2019; Trachalaki 2021; Hou et al. 2021). Mitochondrial dysfunction not only causes excessive ROS production but also promotes inflammasome activation through the release of oxidized mtDNA (Zhong 2018). Studies have shown that cytosolic oxidized mtDNA can directly bind to NLRP3 and facilitate its assembly, and ROS scavengers can effectively suppress this process (Shimada 2012). Additionally, NEK7, a member of the NIMA–related kinase family, has been identified as a key regulator of NLRP3 oligomerization and function. Acting downstream of potassium efflux, NEK7 modulates NLRP3 activation through multiple pathways, including ROS generation, NF-κB activation, and lysosomal stability (He et al. 2016). Thus, NEK7 is considered a potential therapeutic target for regulating NLRP3-related diseases (Liu et al. 2020). Increasing evidence highlights the central role of mitochondria in NLRP3 inflammasome activation. Factors such as mitochondrial uncoupling, NLRP3 deubiquitination, ASC linear ubiquitination, and the release of cardiolipin and mtDNA from mitochondria are all thought to promote NLRP3 translocation to the mitochondrial surface and subsequent inflammasome formation (Liu et al. 2018).

3. The potential of nanotechnology targeting NLRP3 inflammasome in the treatment of inflammation–associated diseases

The NLRP3 inflammasome plays a critical role in the pathogenesis of various inflammation–related diseases. This section explores several major diseases affecting vital human organs or tissues and discusses the therapeutic potential of nanotechnology targeting the NLRP3 inflammasome in these conditions.

3.1. Application of nanotechnology–based NLRP3 targeted therapy in atherosclerosis

Atherosclerosis (AS) is a vascular disease characterized by lipid deposition in the arterial intima and chronic inflammatory responses. It involves progressive narrowing and plaque formation in medium–and large–sized arteries and is a major cause of severe cardiovascular events such as myocardial infarction and ischemic stroke (Bjorkegren and Lusis 2022). Studies have shown that various endogenous danger signals (e.g. cholesterol crystals, oxidized low–density lipoprotein and its metabolites) and exogenous stimuli (e.g. nicotine) can activate the NLRP3 inflammasome in vascular endothelial cells, triggering pyroptosis and the release of pro–inflammatory cytokines–processes pivotal in AS progression (Duewell 2010; Wu 2018; Wang et al. 2020). Notably, sustained activation of the NLRP3 inflammasome not only accelerates the advancement of coronary plaques but also significantly increases plaque vulnerability, thereby elevating the risk of acute myocardial infarction (Toldo and Abbate 2024). In addition, Chen et al. were the first to suggest that NLRP3 inflammasome–induced mitochondrial dysfunction is associated with Ang II–induced cardiomyopathy. Knockout of the NLRP3 gene can significantly alleviate Ang II–induced cardiomyopathy by improving mitochondrial dysfunction and reducing cardiac inflammation, oxidative stress, and fibrosis. Targeting the NLRP3 inflammasome and/or mitochondria may represent a novel therapeutic strategy for Ang II–induced heart disease (Chen 2021).

Therapeutic strategies targeting the NLRP3 inflammasome have shown promising outcomes in both preclinical and clinical settings. These include silencing the expression of inflammasome–related components via gene therapy or blocking NLRP3 activation using selective small–molecule inhibitors, which can effectively reduce infarct size and improve prognosis (Toldo and Abbate 2024). Among these, colchicine (COL)—a classical NLRP3 inhibitor–exerts cardioprotective effects by modulating the NF-κB signaling pathway. However, its clinical utility is limited by a narrow therapeutic window and dose–dependent adverse effects such as myelosuppression and gastrointestinal irritation (Tang 2023).

To address these limitations, Tang et al. developed a VHPK peptide–modified nanoparticle delivery system (VHPK–PLGA@COL) (Figure 3a). This nanoformulation selectively accumulates in inflamed endothelial cells via active targeting, significantly enhancing the bioavailability of COL while effectively modulating the NF-κB/NLRP3 signaling axis to inhibit AS progression and reduce systemic toxicity (Figure 3b, c). Immunofluorescence (IF) staining for CD68 (a macrophage marker) and MMP−9 expression in aortic sinus sections revealed that VHPK–PLGA@COL–treated plaques exhibited a more stable phenotype compared to the free COL and untreated groups, characterized by reduced plaque burden, lipid deposition, macrophage infiltration, and MMP−9 expression (Figure 3d). Histological H&E staining confirmed significant plaque reduction following treatment with COL or VHPK–PLGA@COL (Figure 3d), with the nanoparticle formulation demonstrating a more pronounced effect (Figure 3e). CLSM analysis of DiI–labeled VHPK–PLGA@COL demonstrated specific targeting of inflamed HUVECs (Figure 3f). Western blot results suggested that COL exerts anti–AS effects through inhibition of the NF-κB/NLRP3 pathway, which is further enhanced by the inflammation–targeting and sustained–release properties of the VHPK–modified nanoparticle (Figure 3g). Importantly, histopathological examination of major organs (heart, liver, spleen, lung, kidney) revealed no significant toxicity in mice treated with VHPK–PLGA@COL, indicating its high translational potential (Figure 3h). In addition to this active targeting approach, Liu et al. proposed an alternative strategy using β-glucan–based nanoparticles with intrinsic myocardial tropism. Compared to FDA–approved commercial micelles, this novel formulation–loaded with the NLRP3 inhibitor CY−09—exhibited superior cardioprotective and anti–heart failure effects in a myocardial ischemia–reperfusion (I/R) injury model (Liu 2022), offering a promising direction for next–generation heart–targeted nanomedicines.

Figure 3.

(a) After encapsulating COL in the nanoparticles, the VHPK peptide was subsequently added to target AS, forming VHPK–PLGA@COL. (b) These nanoparticles could accumulate in inflamed endothelial cells that overexpressed VCAM−1 and restrict the progression of AS by inhibiting NF-κB/NLRP3 pathways and reducing the secretion of proinflammatory cytokines such as IL-1β and IL−18. (c) In our study, six–week–old male ApoE −/− mice were divided into 5 groups (G1-G5). In G1, the normal group, mice were fed a normal chow diet (NCD). In G2 to G5, mice were fed a high–cholesterol diet (HCD) for 10 weeks followed by treatment with saline, VHPK–PLGA, COL, or VHPK–PLGA@COL, respectively, for 8 weeks. (d) H&E and ORO–staining, and immunofluorescence studies on the expression of CD68 and MMP−9 on cross–sections of aortic sinus (scale bar = 200 μm). (e) Digital images of the aortic arch (top) and en face micrographs of ORO–stained aortas (bottom) after 8 weeks of treatment. (f) Targeting ability of PLGA@COL and VHPK–PLGA@COL in vitro. HUVECs with or without activation by TNF-α, TNF-α (+) or TNF-α (–), were incubated with DiI–labeled PLGA@COL or VHPK–PLGA@COL for 2 h and images were observed with CLSM. For blocking analysis, activated cells were first treated with VHPK peptide solution followed by incubation with VHPK–PLGA@COL (middle column). (blue = nucleus, red = nanoparticles, scale bar = 50 μm). (g) Western blot (WB) analysis on the expression of p65, NLRP3, caspase−1, IL-1β, and IL−18 proteins in the aortas of different groups of mice after 8 weeks of treatment. (h) H&E staining of the heart, liver, spleen, lung, and kidney of ApoE −/− mice after different treatments (Tang 2023).

3.2. Nanotechnology–enabled NLRP3-targeted therapy in diabetes

In the pathological state of diabetes, a persistent hyperglycemic microenvironment induces redox imbalance, endoplasmic reticulum stress, and chronic low–grade inflammation. These pathological changes collectively activate the molecular mechanisms of pyroptosis, ultimately contributing to the development of chronic diabetic complications (Cheng 2020; Ke et al. 2020). Mechanistically, pyroptosis in diabetes involves NLRP3 inflammasome assembly and activation, cleavage of GSDMD, and the formation of membrane pores, leading to the release of pro–inflammatory cytokines such as IL-1β and IL−18, and ultimately cell lysis (Cao et al. 2022).

Li et al. conducted a comprehensive review delineating the central role of pyroptosis in diabetes and its complications, and emphasized the multitarget regulatory effects of ginsenosides. These natural compounds can modulate key signaling pathways, including the IκB/NF-κB/NLRP3 axis, to effectively suppress pyroptosis, suggesting that NLRP3 is a viable therapeutic target for managing diabetes and its complications (Li et al. 2025).

To address impaired diabetic fracture healing, researchers developed a ROS–responsive multifunctional hydrogel (RPO) incorporating rutin (a natural NLRP3 inhibitor), 3-carboxyphenylboronic acid, and aminated gelatin (collectively termed the RCN compound), as shown in Figure 4a. This delivery system exhibits several advantageous features: (1) injectability and in situ gelation for minimally invasive administration; (2) controlled release of rutin; and (3) dynamic regulation of the local inflammatory microenvironment at the fracture site (Figure 4b). The hydrogel effectively inhibited local NLRP3 activation and significantly accelerated bone regeneration in diabetic rats, offering new insights for clinical treatment of diabetic fractures (Xing 2025).

Figure 4.

(a) Preparation process of RPO hydrogel. (b) Schematic representation of RPO hydrogel responsive release of rutin to promote osteogenic differentiation through immunomodulation. (c, d) Immunofluorescence staining of NLRP3 and IL-1β in different RPO hydrogel treated for 12 h after stimulation with LPS for 15 min and then ATP for 30 min. Scale bar: 100 μm. (e) Heat map analysis of RT–qPCR. (f) Schematic diagram of the inflammatory pathway inhibited by RPO hydrogel. Data are expressed as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 3. (g) ELIZA for quantitative analysis of the expression of NRLP3-relevant inflammatory proteins (IL-1β, IL−18). (h) RT–qPCR of the expression of relevant inflammatory genes (NLRP3, IL-1β, IL−18) in different RPO hydrogel treated for 12 h after stimulation with LPS for 15 min and then ATP for 30 min (Xing 2025).

To evaluate the inhibitory effect of the RPO hydrogel on NLRP3 overactivation, Xing et al. mimicked the immune microenvironment using bone marrow–derived macrophages (BMDMs). Immunofluorescence staining showed that RPO hydrogel significantly downregulated NLRP3 and IL-1β expression after ATP–induced overactivation (Figure 4c, d). ELIZA assays confirmed reduced secretion of IL−18 and IL-1β (Figure 4g), consistent with the IF results. qRT–PCR analysis further demonstrated decreased mRNA levels of NLRP3, IL−18, and IL-1β (Figure 4e, h). Mechanistically, Figure 4f illustrates that the RPO hydrogel alleviates oxidative stress and mitochondrial dysfunction, thereby suppressing NLRP3 hyperactivation. These findings suggest that RPO hydrogel can effectively mitigate NLRP3-mediated inflammation under hyperglycemic conditions.

3.3. Application of nanotechnology–based NLRP3-targeted therapies in gouty arthritis

Gouty arthritis is a common metabolic disease whose pathogenesis mainly involves the activation of the innate immune system by monosodium urate (MSU) crystals, particularly the activation of the NLRP3 inflammasome. This activation induces macrophages and neutrophils to secrete large amounts of IL-1β, triggering a robust inflammatory response and ultimately leading to the onset of gouty arthritis (So and Martinon 2017). As such, the NLRP3 inflammasome plays a pivotal role in the pathological process of gout and has emerged as a crucial therapeutic target. In recent years, researchers have explored natural compounds such as Pulsatilla saponin B4 (B4) and resveratrol (Res) as novel agents for gout treatment by inhibiting NLRP3 activation. Specifically, B4 targets NEK7 and disrupts the NEK7–NLRP3 complex, significantly suppressing MSU–induced inflammation, alleviating macrophage pyroptosis, and lowering serum uric acid levels in mice (Ni 2025). Res, on the other hand, may activate the Pink1/Parkin pathway, promote mitophagy, and inhibit the activation of the NLRP3 inflammasome, thereby exerting therapeutic effects on gouty arthritis (Fan et al. 2021). These findings offer new strategies and approaches for the prevention and treatment of gout.

Recently, Xu et al. integrated resveratrol with nanotechnology to develop a mitochondria–targeted, multi–functional intelligent nanoplatform. They designed a novel nanozyme (PtHD) with excellent dispersibility, stability, photothermal, anti–inflammatory, and immunomodulatory properties, and constructed a liposomal nanoreactor (D-N) (Xu 2024) (Figure 5Ia). As shown in Figure 5Ib, c, the nanoreactor consists of a water–soluble and water–dispersible URI–PtHD cascade nanozyme core and a lipophilic resveratrol–containing lipid shell. The system was further encapsulated with EM2 to obtain D-N[EM2], allowing immune camouflage, targeted cellular uptake, and lysosomal escape for precise drug delivery to inflamed joints. Western blot analysis demonstrated that D-N[EM2] treatment significantly reduced the expression of key signaling molecules, including pro–caspase−1, NLRP3, and NF-κB, while upregulating SIRT1 in MSU–stimulated RAW 264.7 cells. Notably, biomimetic nanocarrier systems based on cell membrane technology have also made groundbreaking progress in gouty arthritis therapy. These platforms retain natural membrane interfaces, offering advantages such as immune evasion and prolonged circulation. For example, Chen et al. developed a biomimetic hybrid liposome cloaked with M2 macrophage–red blood cell hybrid membranes (USM[H]L) to target inflamed joints and reprogram the inflammatory immune activation microenvironment (IIME), thereby enhancing enzymatic thermotherapy for gouty arthritis (Freeman et al. 2017) (Figure 5II). Collectively, these studies underscore the great potential of nanotechnology in targeting NLRP3 for treating inflammation–related metabolic diseases.

Figure 5.

(I) Schematic illustration of inflammation–targeting M2-macrophage–derived hybrid exosome–cloaked nanocarrier, useful to simultaneously lower uric acid, achieve anti–inflammation and reprogram the IIME for multimodal enzyme hyperthermia immunotherapy of GA. a, Synthesis pathway of PtHD, D-N and D-N[EM2]. b, In the circulation systems of gouty rats, D-N[EM2] reprogrammed M1 macrophages to M2 macrophages, exhibited prolonged retention time and decreased immunogenicity. c, Multimodal therapeutic modality mechanisms of D-N[EM2]. NIR, near infrared (Xu 2024). (II) Schematic illustration of manipulated endogenous IAM–targeted biomimetic M2 macrophage–erythrocyte–cloaked nanosome to decrease urate and inflammatory levels simultaneously and reprogram IIME for enzyme–thermo–immunotherapy of GA. a) Schematic design of the cascade bienzymes and MTX–loaded biomimetic M2 macrophage–erythrocyte–cloaked nanosome (USM[H]L). b) Schematic illustration of four properties of USM[H]L. c) Schematic illustration of the endogenous IAM–targeted USM[H]L for co–therapy by reprogramming IIME (Freeman et al. 2017).

3.4. Application of nanotechnology–based NLRP3-targeted therapies in central nervous system disorders

Neuroinflammation is a hallmark pathological feature shared by many central nervous system (CNS) disorders, in which the NLRP3 inflammasome plays a critical role (Freeman et al. 2017). Studies have shown that in conditions such as stroke, traumatic brain injury, Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis, abnormal activation of the NF-κB signaling pathway significantly upregulates the expression of NLRP3 and pro–inflammatory cytokines (pro–IL-1β, pro–IL−18), subsequently triggering pyroptosis and a cascade of inflammatory responses (Swanson et al. 2019). Notably, in neurodegenerative diseases such as AD and PD, pathological proteins (e.g. Aβ and α-synuclein) can directly activate the NLRP3 inflammasome. They also exacerbate activation by disrupting mitochondrial function (causing a 60–70% reduction in mitochondrial membrane potential) and increasing reactive oxygen species (ROS) production (by 2–3 times) (Heneka et al. 2018). The positive feedback loop between protein aggregation and NLRP3 activation constitutes a major driving force in disease progression (McManus 2025). Although small–molecule NLRP3 inhibitors (e.g. MCC950) have shown promising effects in preclinical studies, their clinical application is hindered by the blood–brain barrier (BBB) (Heneka et al. 2018; Haque et al. 2020; Singh 2022). For example, although FTY720 has been approved by the FDA for multiple sclerosis, its limited brain bioavailability and potential side effects (e.g. bradycardia at high doses) pose significant challenges.

To overcome this, Zhao et al. developed a ROS–responsive drug delivery platform by coating nanoparticles with neutrophil membranes. This nanoplatform demonstrated enhanced BBB permeability and accumulated in ischemic brain tissue through interaction with inflamed brain microvascular endothelial cells (Zhao 2024). Indeed, the potential of nanotechnology in treating CNS diseases goes far beyond drug delivery. He et al. designed a liposomal formulation encapsulating felodipine (felodipine@LND) that uses low–intensity pulsed ultrasound (LIPUS) to assist BBB penetration for AD treatment. Felodipine@LND suppressed NLRP3 activation, promoted Aβ degradation by BV2 microglia, inhibited CALR translocation, and reduced NLRP3 inflammasome activation (He 2024) (Figure 6a). To validate its protective effect, BV2 microglia were incubated with Aβ oligomers (oAβ). As shown in Figure 6b and c, felodipine@LND significantly reduced Aβ deposition. Western blot (Figure 6d and e) and immunofluorescence staining (Figure 6f and g) revealed that CALR mislocalization was alleviated after felodipine@LND treatment. Moreover, expression of NLRP3, p-NFκB, and ASC was significantly upregulated following oAβ exposure (p = 0.0001, p < 0.0001, p = 0.0009), but markedly suppressed by felodipine@LND (p = 0.0105, p < 0.0001, p < 0.0001) (Figure 6h–k). In another study, Prussian blue nanozyme (PBzyme) attenuated neurodegeneration in PD mouse and cellular models by scavenging ROS, thereby reducing activation of microglial NLRP3 inflammasome and caspase−1, suppressing GSDMD cleavage and proinflammatory cytokine release, and ultimately inhibiting microglial pyroptosis (Ma et al. 2022).

Figure 6.

(a) Illustration of the study design. Preparation and LIPUS–assisted delivery of felodipine nanodrug (felodipine@LND). Proposed mechanism of felodipine@LND crossing the BBB to mitigate the anxiety–like behavior and cognitive impairment. (b) Immunofluorescent images showing microglial phagocytosis of Aβ plaques. (c) Quantitative analysis of Aβ plaques that were not degraded by microglia. (d,e) Representative blots and quantitative analysis of CALR in BV2 cells treated with or without either oAβ plus PBS, oAβ plus blank LNP, oAβ plus felodipine@LND, blank LNP or felodipine@LND. (f) Immunofluorescent images for microglial CALR, showing how cell surface translocation of CALR was induced by oAβ and inhibited by felodipine@LND. (g) Quantitative analysis of CALR intensities in BV2 cells. (h,i) Representative blots and quantitative analysis of NLRP3 (i), phosphorylated NFκB (p-NFκB) (ii), and ASC (iii) in BV2 cells treated with or without oAβ plus PBS, oAβ plus blank LNP, Aβ plus felodipine@LND, blank LNP or felodipine@LND. (j,k). Representative blots and quantitative analysis of Caspase−1 (i), Cleaved caspase−1 (ii), Pro–IL 1β and mature IL 1β (iii) in BV2 cells treated with or without oAβ plus PBS, oAβ plus blank LNP, oAβ plus felodipine@LND, blank LNP or felodipine@LND. Data are shown as mean ± SD, n = 4; means ± SD; ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05) (He 2024).

It is also worth noting that nanotechnology holds great promise in the diagnosis of CNS disorders. For example, a curcumin–based theranostic nanoplatform has been developed for the sensitive detection and clearance of Aβ plaques via magnetic resonance imaging (MRI). Moreover, by suppressing NLRP3 activation, this platform reverses cognitive impairment caused by AD, offering new therapeutic possibilities (Ruan 2022).

3.5. Application of nanotechnology–based NLRP3-targeted therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction, synovitis, and damage to cartilage and bone, which may ultimately lead to joint deformity and functional disability (Smolen et al. 2016). Recent studies have demonstrated that the NLRP3 inflammasome plays a crucial role in the pathogenesis of RA. Elevated intracellular levels of NLRP3, activated caspase−1, pro–IL-1β, and active IL-1β have been detected in whole blood cells of patients with active RA (Choulaki 2015). Further confirmation was provided by Guo et al., who showed that MCC950 effectively inhibits the activation of the NLRP3 inflammasome in monocytes and macrophages, thereby alleviating arthritis, inflammation, and bone damage (Guo 2018). These findings provide compelling evidence for the pivotal role of the NLRP3 inflammasome in RA.

Chrysin, a potential anti–inflammatory compound, has been shown to alleviate osteoarthritis in rats by inhibiting the NLRP3 inflammasome. However, its poor physicochemical properties and non–specific biodistribution limit its therapeutic efficacy. To address these issues, researchers developed a biomimetic nanocarrier (FMPlipo@C) to enhance the targeted delivery of chrysin to synovial cells. This system significantly reduced inflammation in collagen–induced arthritis (CIA) mice by inhibiting the HIF-1α/iNOS/NLRP3 pathway (Chen et al. 2025).

Chen et al. designed a multifunctional nanosystem, TPC–U@HAT, for RA therapy. This system offers multi–target, dual–responsive, and on–demand drug release capabilities. TPC–U@HAT comprises the probe/prodrug TPC, the JAK1 inhibitor upadacitinib, and the drug carrier HAT. TPC consists of an aggregation–induced emission (AIE)-active NIR–II fluorophore (TPY) and the NF-κB/NLRP3 inhibitor caffeic acid phenethyl ester (CAPE), linked via a boronic ester bond to form a reactive oxygen species (ROS)-responsive linker (Figure 7a and b). Following intravenous injection, TPC–U@HAT accumulates in inflamed RA lesions through both active and passive targeting (Figure 7c, d, and e), releasing CAPE and upadacitinib to exert therapeutic effects by inhibiting the NF-κB/NLRP3 and JAK–STAT pathways (Figure 7f, g, and h) (Chen et al. 2024). In summary, the NLRP3 inflammasome plays a key role in RA pathogenesis. Nanotechnology–based therapeutic strategies targeting this pathway offer promising new directions for RA treatment.

Figure 7.

(a) fabrication of the nanosystem TPC–U@HAT and (b) the multitargeting, dual–biomarkers–responsive detection/imaging and therapy for rheumatoid arthritis. (c) NIR–II fluorescent images of the ZIA mice (zymosan dose of 25 mg·kg⁻¹) and the control at various time points following the i.v. injection of TPC, TPC@HT, or TPC@HAT. Mice in prone posture during imaging experiment. Excitation wavelength: 808 nm. (d) Average NIR–II fluorescent intensities of the ankle joint area (ROI, green circle) in the mice of (c). (e) NIR–II fluorescent images for the left legs from different groups at 4 h upon i.v. injection of different formulations. Excitation wavelength: 808 nm. (f) Notation with colors and marks for each group. (g) Expression levels of serum IL−6, TNF-α, and IL-1β of different groups at day 60. (h) p-STAT1, NLRP3, and NF-κB levels in ankle joint tissues assessed by Western blotting analyzes for G1–G6. Histones H3 as the loading control for nuclear protein, and β-actin as the loading control for cytosolic protein. Data: the mean ± SD (Chen et al. 2024).

3.6. Application of nanotechnology–based NLRP3-targeted therapy in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic chronic autoimmune disease characterized by the production of multiple autoantibodies, immune complex deposition, and dysregulated immune responses, leading to multiorgan damage (Tsokos et al. 2016). Recent studies have shown that the NLRP3 inflammasome plays a critical role in the pathogenesis and progression of SLE. For instance, elevated expression of the NLRP3 inflammasome has been observed in renal tubular cells and podocytes of SLE patients, and this upregulation correlates positively with disease activity indicators such as proteinuria (Fu 2017). Moreover, anti–double–stranded DNA (dsDNA) antibodies–hallmark antibodies in SLE–can activate the TLR4/NF-κB pathway via the induction of mitochondrial reactive oxygen species (ROS), subsequently triggering NLRP3 inflammasome activation in macrophages (Zhang 2016). These findings highlight the central role of the NLRP3 inflammasome in SLE immunopathology.

Although conventional treatments such as glucocorticoids and immunosuppressants are widely used for SLE, they remain limited in rapidly eliminating pathogenic antibodies. To address this, Liu et al. developed DNA–modified mesoporous silica nanoparticles loaded with organoselenium (MSNs–DNA@SeC). These nanoparticles utilize surface–modified ctDNA to specifically bind anti–dsDNA antibodies while leveraging the immunomodulatory functions of selenium, thereby enabling efficient clearance of pathogenic antibodies and remodeling of the immune microenvironment (Liu 2025). This innovative approach offers a new avenue for SLE therapy.

In parallel, with the rapid advancement of nanotechnology, nanocarrier–based drug delivery strategies for SLE have also made substantial progress. Given the challenges of inadequate drug accumulation at target sites and increased systemic toxicity in conventional systemic delivery of immunomodulators, researchers have designed dual–specificity ICOS/CD40L nanoparticles encapsulating rapamycin (RAP) to achieve disease–specific multi–target therapy (Zhang 2022). This novel delivery system overcomes the limitations of traditional therapies and opens new possibilities for precision treatment of SLE.

Furthermore, bone marrow–derived mesenchymal stem cells (BMSCs) have been shown to alleviate SLE symptoms by inhibiting NLRP3 inflammasome activation through the Pim−1 kinase pathway (Yu et al. 2024). This raises the possibility of developing a novel nanotherapeutic approach by combining nanotechnology with BMSCs. Specifically, mesenchymal stem cell membrane–coated nanoparticles (MSC–NPs) could be engineered to possess both high–efficiency delivery of anti–inflammatory agents and the inherent anti–NLRP3 activity of BMSCs. These MSC–NPs would retain the immunomodulatory properties of BMSCs via their surface membrane, including suppression of NLRP3 inflammasome activation and immune microenvironment regulation. Meanwhile, the nanoparticle core could encapsulate anti–inflammatory drugs (e.g. rapamycin or other immunomodulators) for targeted delivery and controlled release. This dual–functional design not only enhances drug accumulation at lesion sites but also amplifies anti–inflammatory effects through the intrinsic features of BMSCs, thereby improving therapeutic efficacy while minimizing systemic toxicity. Future research should further explore the fabrication processes, pharmacodynamic properties (both in vitro and in vivo), and clinical translation potential of MSC–NPs to offer safer and more effective therapeutic solutions for autoimmune diseases.

3.7. Application of nanotechnology–based NLRP3-targeted therapy in inflammatory bowel disease

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a complex disorder characterized by chronic, relapsing inflammation of the gastrointestinal tract (Goyette et al. 2007). Although the exact etiology and pathogenesis of IBD remain incompletely understood, numerous studies have demonstrated a critical role for the NLRP3 inflammasome in the disease process (Zhang et al. 2023). Activation of the NLRP3 inflammasome is considered an important trigger for the onset and relapse of colitis. It has been observed that NLRP3 inflammasome activity increases significantly prior to colitis flare–ups, and aberrant activation and upregulation of the inflammasome have been detected in the colonic tissues of IBD patients, with its activity progressively increasing with disease progression (Liu 2017; Chen et al. 2020; Sun et al. 2022). Thus, the NLRP3 inflammasome has emerged as a highly promising therapeutic target for IBD.

Conventional treatments for IBD, such as anti–inflammatory drugs and immunosuppressants, suffer from poor targeting, systemic toxicity, and a high rate of relapse. The rapid advancement of nanotechnology offers novel solutions for precise IBD therapy. Sun et al. combined nanotechnology with NLRP3 inhibitors to develop an oral nanoplatform (QM@EP) for colitis detection, targeted drug delivery/release, and therapy. QM@EP is composed of the molecular probe QY–SN–H₂O₂, the NLRP3 inhibitor MCC950, and an enteric polymer. Triggered by the colonic pH, the nanoplatform disassembles, releasing both the probe and the NLRP3 inhibitor in the colon (Figure 8a). On one hand, the released NLRP3 inhibitor exerts therapeutic effects; on the other, pathological colonic H₂O₂ cleaves the pentafluorobenzenesulfonate group in QY–SN–H₂O₂, producing an AIE–active chromophore QY–SN–OH for NIR–II fluorescence and photoacoustic imaging (Figure 8b) (Sun et al. 2022). Western blot analysis (Figure 8c) confirmed that QM@EP can effectively inhibit the NLRP3 inflammasome, yielding satisfactory therapeutic outcomes for UC. The levels of TNF-α and IL−6 in colonic tissue were also assessed (Figures 8d and e). Compared with healthy controls, the upregulation of pro–inflammatory cytokines in the UC + QM@EP group was significantly reversed. Furthermore, H&E staining of colonic tissues from different groups (Figure 8f) further demonstrated the local therapeutic effect of MCC950 in the UC + QM@EP group. Additionally, Hou et al. successfully constructed novel antioxidant nanomaterials capable of specifically targeting inflamed colonic tissue and effectively clearing ROS via oral administration, thereby achieving high therapeutic efficacy against DSS–induced colitis and significantly suppressing inflammation to alleviate colitis symptoms (Hou 2022).

Figure 8.

(a) Schematic illustration of multiple actions of the oral–administration theranostic nanosystem QM@EP, including colon–targeted delivery and release of payloads upon being triggered by colonic pH, diagnosis of ulcerative colitis upon being triggered by pathological colonic H2O2 through NIR–II fluorescent imaging and 3D MSOT imaging, as well as efficient therapy against ulcerative colitis via suppressing NLRP3 inflammasome. (b) The chemical structures of the activatable probe QY–SN–H2O2 and the AIEgen QY–SN–OH generated upon the probe's response toward H2O2. (c) Western blot analyzes for NLRP3 inflammasome levels in colonic tissues of the mice from different groups on day 11. β-actin acts as the protein loading control. (d) Relative TNF-α levels in colonic tissues from the mice of different groups measured by using ELIZA kits on day 11 (n = 6). (e) Relative IL−6 levels in colonic tissues from the mice of different groups measured by using ELIZA kits on day 11 (n = 6). (f) H&E staining analyzes' results of the colon sections from the mice of different groups on day 11. Scale bar = 100 μm (Sun et al. 2022).

3.8. Application of nanotechnology–based NLRP3-targeted therapy in liver diseases

Liver diseases are complex conditions driven by pro–inflammatory cascades in the liver and systemic circulation, primarily mediated by innate immune cells. The pathological processes involve inflammation, fibrosis, hepatocyte damage, and impaired regeneration (Del Campo et al. 2018). In patients with liver cirrhosis, the expression of the NLRP3 inflammasome and its downstream effector caspase−1 is significantly increased in hepatic tissue, indicating the critical role of NLRP3 in the onset and progression of liver diseases (Ma et al. 2018). In recent years, the NLRP3 inflammasome has become a promising therapeutic target for chronic liver diseases due to its central role in inflammation and pyroptosis. Nanotechnology–based NLRP3-targeted therapies offer new strategies for precise intervention in liver diseases.

Zhan et al. developed a dopamine precursor–based nanoprodrug system (SW@DSeSeD) (Figure 9a) capable of in situ drug release in the liver, inhibiting the NLRP3 inflammasome and promoting liver regeneration for the treatment of acute liver failure (ALF) (Zhan et al. 2021). As shown in Figure 9b and c, SW@DSeSeD treatment significantly reduced levels of p-JNK, cleaved caspase−3, NLRP3, and 15-PGDH. Liver congestion and surface roughness, indicative of liver damage, were notably alleviated following SW@DSeSeD treatment (Figure 9d), demonstrating its high efficacy in ALF therapy. Considering the pivotal role of mitochondrial ROS (mtROS) in NLRP3 activation, researchers also developed mitochondria–targeted antioxidant nanomaterials. For example, tannic acid (TA) was assembled with superoxide dismutase (SOD) and catalase (CAT) into a complex (TSC), specifically targeting mitochondria and efficiently eliminating mtROS (Zhang 2023). This nanocomposite effectively reversed mitochondrial depolarization and suppressed NLRP3-mediated pyroptosis, significantly alleviating hepatitis and related liver injury.

Figure 9.

(a) Schematic representation of combination therapy for acute liver failure in mouse model by using SW@DSeSeD nanodrug via inhibiting further liver damage (through blocking NLRP3 inflammasome activation) as well as facilitating liver regeneration (through inhibiting prostaglandin–degrading enzyme 15-PGDH). A dye–doped nanoparticle (ICG–SW@DSeSeD) can be utilized for multi–mode imaging. (b) Western blotting analyzes illustrating the level of p-JNK, caspase 3, NLRP3 and 15-PGDH in liver tissues dissected from the control (WT) and different treatment groups after euthanasia: APAP injection (200 mg kg⁻¹ or 300 mg kg⁻¹) only, and treatment with dopamine, SW, DSeSeD NPs or SW@DSeSeD NPs after injection of 300 mg kg⁻¹ APAP. All data are represented as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001. (c) representative H&E staining and IHC analyzes (caspase−3 and Ki67) for different groups. Scale bar: 200 μm for H&E and 100 μm for IHC. (d) Representative photographs of dissected liver from WT, untreated ALF or SW@DSeSeD–treated ALF mouse after euthanasia (Zhan et al. 2021).

3.9. Application of nanotechnology–based NLRP3-targeted therapy in sepsis

Sepsis is a systemic inflammatory response syndrome triggered by infection, characterized by immune dysregulation, cytokine storm, and multi–organ dysfunction (Wiersinga et al. 2014). In the early stages of sepsis, pathogen–associated molecular patterns (PAMPs) and damage–associated molecular patterns (DAMPs) are released, recruiting and activating immune cells and triggering inflammatory responses (Kuzmich et al. 2017). As key pattern recognition receptors (PRRs), Toll–like receptors (TLRs) play crucial roles in microbial recognition and immune regulation. The NLRP3 inflammasome, a central regulator of intracellular inflammatory signaling, senses both PAMPs and DAMPs, and activates caspase−1 via ASC recruitment to facilitate cytokine maturation and release, thereby exacerbating sepsis pathophysiology (Danielski et al. 2020; He et al. 2023).

Studies have shown that dihydromyricetin can alleviate sepsis–induced acute lung injury (ALI) by inhibiting NLRP3 inflammasome–dependent pyroptosis (Wang 2019). Furthermore, Wang et al. found that the expression of C3/C3a and its receptor C3aR was significantly elevated in septic mice, and that blocking the C3a–C3aR signaling pathway reduced pulmonary endothelial pyroptosis by inhibiting NLRP3/caspase−1 and caspase−11 pathways, thereby ameliorating sepsis–induced ALI (Li 2022). These findings highlight the pivotal role of the NLRP3 inflammasome in sepsis and provide a theoretical basis for targeted therapy.

Recent advances in nanotechnology have enabled innovative approaches to NLRP3-targeted sepsis therapy. For example, Ye et al. designed a series of nanoparticles (NPs) loaded with NAD⁺ and its reduced form (NADH), which can be directly delivered to the cytoplasm to exert potent immunomodulatory effects. These NPs block both canonical and non–canonical NLRP3 inflammasome activation pathways, demonstrating excellent efficacy in treating endotoxemia and multidrug–resistant pathogen–induced bacteremia (Ye 2022). Additionally, Du et al. developed a multifunctional decoy nanozyme by cloaking mesoporous silica nanoparticles (MSNs) loaded with Ce6 photosensitizers and CeO₂ nano–catalysts with macrophage membranes. This nanozyme neutralizes endotoxins and sequesters pro–inflammatory cytokines, rapidly scavenges reactive oxygen species (ROS) via enzymatic catalysis, and mitigates systemic oxidative stress and tissue injury, thereby protecting host immune cells from excessive activation (Du 2022). Importantly, nanomedicine delivery platforms also enhance drug bioavailability and effective concentrations, offering promising new strategies for sepsis treatment (Zhou et al. 2025).

4. Mechanistic studies of nanoparticle–based targeted therapy strategies for the NLRP3 inflammasome in inflammation–related diseases

Nanoparticles regulate the NLRP3 inflammasome through multiple mechanisms, offering novel strategies for the treatment of inflammatory diseases. These nanomaterials can directly inhibit inflammasome assembly and activation, and act as drug delivery systems to enhance targeting and bioavailability. Furthermore, nanoparticles can suppress inflammasome activation by modulating intracellular oxidative stress and ionic homeostasis. Overall, nanotechnology provides innovative approaches to target the NLRP3 inflammasome via diverse mechanisms.

4.1. Multifaceted roles of nanoparticles in inhibiting NLRP3 inflammasome activation

4.1.1. Nanoparticles inhibit the assembly of the NLRP3 inflammasome

Nanomaterials can interfere with the assembly of the NLRP3 inflammasome by interacting with NLRP3 or associated proteins, thereby preventing the formation of the active complex. Chen et al. (Chen 2021) demonstrated that miR−4057 encapsulated in honey–derived vesicle–like nanoparticles significantly suppressed the formation and activation of the NLRP3 inflammasome, exerting strong anti–inflammatory effects in a mouse model of acute liver injury. The underlying mechanism involved inhibition of ASC oligomerization, thereby disrupting inflammasome platform assembly. Similarly, garlic chive–derived vesicle–like nanoparticles (GC–VLNs) (Liu 2021) and ginger rhizome–derived exosome–like nanoparticles (G–ELNs) (Chen et al. 2019) exhibited notable anti–NLRP3 activity in primary macrophages. Immunofluorescence staining and ASC oligomerization assays confirmed that GC–VLNs reduced ASC speck formation in macrophages by preventing ASC oligomerization. Additionally, nickel–cobalt alloy nanocrystals (NiCo NCs) inhibited the activation of NLRP3, NLRC4, and AIM2 inflammasomes via downregulation of Neat1 transcription, ultimately preventing ASC speck formation (Lin 2023) (Figure 10a). In studies exploring NiCo NCs' inhibition of NLRP3 activation, NiCo NC pretreatment reduced Nigericin–induced caspase−1 activation and maturation of IL-1β and IL−18 in LPS–primed bone marrow–derived macrophages (BMDMs) (Figure 10e–g). Interestingly, ASC expression was unaffected by NiCo NC treatment (Figure 10b, e), while ASC oligomerization and speck formation were significantly suppressed, as shown by immunoblot and immunofluorescence analyzes (Figure 10c, d). These findings indicate that NiCo NCs inhibit NLRP3 inflammasome activation by reducing ASC speck formation.

Figure 10.

(a) Schematic illustration for inhibition of NLRP3, NLRP4 and AIM2 inflammasome activation by NiCo NCs. NiCo NCs inhibited activations of inflammasomes induced by different agonizts. We used RNA sequencing to search for the mechanism by which NiCo NCs broadly inhibit inflammasomes activation. Neat1, a long noncoding RNA that has been reported to bind to NLRP3, NLRC4 and AIM2 inflammasomes to enhance their assembly, was found to be significantly downregulated after NiCo NCs treatment. (b and e) LPS–primed BMDMs were treated with different doses of NiCo NCs and then stimulated with nigericin. Medium supernatant (SN) and cell lysis (Input) were analyzed by immunoblotting for mature IL-1β (mIL-1β), activated caspase−1 (p20), pro–IL-1β and pro–caspase−1. (c) LPS–primed BMDMs were pretreated with 30 μg/mL of NiCo NCs and then stimulated with nigericin, salmonella or poly (dA: dT). Cell lysis (Input) and cross–linked cytosolic pellets were analyzed by immunoblotting. Blank = BMDMs without LPS–priming, Mock = LPS–primed BMDMs without stimulation. (d) Anti–ASC immunofluorescence analysis of LPS–primed BMDMs were treated as in (c). The white arrow indicates example of ASC specks. (e–g) Supernatants were also analyzed by ELIZA for (d) IL-1β, (f) IL−18 and (g) TNF-α release (Lin 2023).

4.1.2. Nanoparticles modulate upstream signaling pathways of NLRP3 activation

Nanotechnology offers distinct advantages in regulating upstream signaling pathways. Firstly, nanoparticles can inhibit NF-κB/p65 nuclear translocation, thereby blocking the NF-κB pathway and reducing the expression of NLRP3 and pro–IL-1β, ultimately inhibiting inflammasome assembly and proinflammatory cytokine production (Qi 2022). For example, biomimetic membrane–coated Prussian blue nanoparticles (PB NPs) showed strong therapeutic effects in atherosclerosis by scavenging ROS and NO, and inhibiting lipid accumulation via suppression of the NF-κB/NLRP3 pathway (Zhou 2022). Secondly, nanotechnology can be combined with gene–editing tools to selectively knock out upstream regulators of NLRP3. Fu et al. (Fu et al. 2023) developed an anionic nanoparticle–based CRISPR/Cas9 delivery system that successfully achieved targeted editing of the PAR2 gene. Co–culture experiments with Raw264.7 macrophages and 4T1 breast cancer cells demonstrated that tBSA/Cas9-PAR2 significantly downregulated NLRP3 and IL-1β expression, effectively suppressing inflammasome signaling in the inflammatory microenvironment.

Notably, in the field of sepsis therapy, researchers developed an innovative nanodrug (HMPDA) (Figure 11Ia) that simultaneously inhibits pyroptosis, inflammatory signaling, and mitochondrial apoptosis pathways (Figure 11Ib). Western blot and immunofluorescence analyzes (Figure 11II) revealed that HMPDA suppresses NF-κB signaling to prevent NLRP3 activation and downstream cascades, ultimately restoring intracellular homeostasis (Yan 2023). These studies highlight the tremendous potential of nanotechnology in modulating inflammasome–related signaling, offering new therapeutic avenues for inflammatory diseases.

Figure 11.

(I) a) Schematic diagram of preparation of HMPDA@BA/NAD + @LSA NPs. B) Therapeutic mechanism of BA–AM and NAD + co–loaded NPs in an LPS–induced sepsis mouse model. (Yan 2023) (II) a) Western blotting analysis of NF-κB expression and semiquantitative results. Data are mean ± SD, n = 3. b) Immunofluorescent staining images of NLRP3 in the liver, kidney, and lung (red fluorescence: NLRP3; blue fluorescence: cell nucleus). Data are mean ± SD, n = 6. c) Western blotting analysis of NLRP3 expression and semiquantitative results. Data are mean ± SD, n = 3. d) Immunofluorescent staining images of the ASC of the liver, kidney, and lung (green fluorescence: the ASC; blue fluorescence: the cell nucleus). Data are mean ± SD, n = 6. Western blotting analysis of e) Casp−1, f) TNF-α, g) IL−6, and h) IL-1β expression and semiquantitative results. 1–5 represent the control group, the sepsis (PBS) group, the HMPDA@LSA group, the HMPDA@NAD + @LSA group, and the HMPDA@BA/NAD + @LSA group, respectively. Data are mean ± SD, n = 3 (Yan 2023).

4.1.3. Nanoparticles suppress NLRP3 inflammasome activation via ROS scavenging

ROS plays a pivotal role in activating the NLRP3 inflammasome (Huang et al. 2021; Ma 2023). Nanomaterials capable of scavenging ROS can effectively inhibit NLRP3 activation and alleviate inflammation. Fullerene nanoparticles, owing to their excellent ROS scavenging capacity, significantly suppressed NLRP3 activation and reduced mature IL-1β secretion and neutrophil infiltration (Liu 2020). Two–dimensional cobalt hydroxide nanosheets (Co NSs) exhibited multi–enzyme–like activity and effectively inhibited NLRP3 activation by eliminating ROS, suppressing NLRP3 oligomerization and ASC speck formation (Figure 12a). They demonstrated potent anti–inflammatory effects in systemic inflammation (Figure 12c, d) and murine colitis models (Figure 12b) (Chen 2023). ELIZA and supernatant quantification assays confirmed that Co NSs dose–dependently decreased bioactive IL-1β and IL−18 levels (Figure 12f, g). Western blotting further validated that Co NSs strongly inhibited NLRP3 inflammasome activation (Figure 12e), while TNF-α production remained unaffected (Figure 12h), indicating that Co NSs specifically block Nigericin–induced NLRP3 activation. Co NSs also significantly reduced cell death in Nigericin–treated BMDMs (Figure 12i). Collectively, Co NSs mitigate pyroptosis by scavenging ROS and inhibiting NLRP3 activation. Additionally, Zhu et al. (Zhu 2024) developed an oral pyroptosis–targeting nanoinhibitor (DCMP) that responds to ROS and releases drugs at sites of intestinal inflammation, suppressing NLRP3 activation and GSDMD cleavage to prevent cell death. Li et al. (Li 2024) designed oral nanomaterials capable of scavenging both TNF-α and ROS to treat intestinal and mesenteric inflammation. In this system, the silica component scavenged ROS and blocked the NLRP3/GSDMD–mediated pyroptotic pathway in intestinal epithelial cells.

Figure 12.

(a) Schematic illustration of Co NSs as a NLRP3 inhibitor for the treatment of systemic inflammation and colitis. Synthesized by a simple method, Co NSs are equipped with multiple enzyme–like and broad–spectrum ROS scavenging properties. Owing to the robust ROS scavenging and oligomerization inhibiting ability, Co NSs exhibit NLRP3 inflammasome inhibition and anti–inflammation effect in both systemic inflammation and colitis mouse models. (b) immunohistochemistry measurement of F4/80 + macrophages as well as histological analysis of colonic tissue sections were performed. Bars for 100 µm. Mean ± SEM. n = 5, **p < 0.01, ***p < 0.001. Student's t–test. Control mice received water without DSS. Co NSs was abbreviated as Co in the figures. (c,d) Serum (c) and peritoneal fluids (d) levels of IL-1β from C57BL/6 mice pretreated with Co NSs or vehicle control as measured by ELIZA 4 h after i.p. LPS injection. In the acute colitis model, C57BL/6 mice were fed with 2.5% DSS in drinking water for 7 days, followed by normal drinking water for 3 days. (e) Corresponding western blot analysis of mature IL-1β (mIL-1β), cleaved caspase−1 (p20) in SN and NLRP3, pro–IL-1β, pro–caspase−1(pro–casp1), ASC in lysates (Input) of BMDMs. (f) IL-1β and (g) IL−18 production in culture supernatants (SN) were measured by ELIZA. (h) TNF-α production (as measured by ELIZA) in supernatant (SN). (i) Fluorescent microscopic images of BMDM cells with different treatments stained by Calcein–AM/PI. Scale bar for 100 µm (Chen 2023).

4.1.4. Inhibition of NLRP3 inflammasome activation via calcium modulation and disruption of NLRP3-NEK7 interaction by nanoparticles

Nanotechnology exhibits significant advantages in regulating intracellular calcium signaling, which plays a crucial role in the assembly and activation of the NLRP3 inflammasome. It has been demonstrated that lanthanide–based nanoparticles coated with peptides can inhibit macrophage inflammasome activation by suppressing ROS generation and TRPM2-mediated Ca²⁺ influx (Yao 2016). Additionally, SkQ1 nanoparticles enhance mitochondrial stability, markedly reduce mitochondrial ROS production and mtDNA oxidation, thereby inhibiting caspase−1–dependent NLRP3 activation and subsequently suppressing IL-1β maturation and secretion (Huang 2024).

Notably, nanotechnology can also modulate NLRP3 inflammasome activation via alternative mechanisms. For instance, gold nanoparticles (Au NPs) attenuate NLRP3 activation by stabilizing lysosomal membranes and inhibiting ROS release, thereby disrupting the NLRP3-NEK7 interaction, which is essential for IL-1β release and tumor progression (Figure 13a) (Zhu 2024). NEK7, a serine/threonine kinase, is indispensable for the assembly and activation of the NLRP3 inflammasome through its interaction with the leucine–rich repeat (LRR) domain of NLRP3 (Sharif 2019).

Figure 13.

(a) A graphical abstract of Au–H6 NPs as a nanomedicine for reducing MDSCs of tumor environment and enhancing PD−1 immunotherapy. (b) Immunoblot analysis showing NLRP3, NF-κB, and p–NF–κB in the cell lysate (lysis) with doses of BMDMs. (c) Fluorescence images of BMDMs that were LPS–primed for 3 h, then treated with DMSO (Mock) Nigericin (Nigericin) or Nigericin plus different size Au NPs (Nigericin + Au NPs) for another 6 h and stained with DCFH–DA (Green) for detecting ROS with another 30 min. Scale bar, 20 μm. (d) Fluorescence images of BMDMs that were LPS–primed for 3 h, then treated with DMSO (Mock) Nigericin (Nigericin) or Nigericin plus different size Au NPs (Nigericin + Au NPs) for another 6 h and stained with mitosox (Red) for detecting mitochondria ROS with another 30 min. Scale bar, 20 μm. (e) Cell lysates from BMDMs were immunoprecipitated by an NLRP3-specific antibody, followed by immunoblotting with an NLRP3 antibody, NEK7 antibody, and ASC antibody. The cells were LPS–primed for 3 h, LPS–primed for 3 h followed by Nigericin challenge for 30 min, or LPS–primed for 3 h then treated with Au NPs for 6 h followed by Nigericin challenge for 30 min. (f) Cell lysates from BMDMs were immunoprecipitated by NEK7 specific antibody and immunoblotting with an NLRP3 antibody, NEK7 antibody, and ASC antibody. The cells were LPS–primed for 3 h, LPS–primed for 3 h followed by Nigericin challenge for 30 min, or LPS–primed for 3 h then treated with Au NPs for 6 h followed by Nigericin challenge for 30 min. (g) Proximity ligation Assay (PLA) of NLRP3-NEK7 interaction in BMDMs that were LPS–primed for 3 h (Mock), LPS plus Nigericin (Nigericin), or LPS plus Nigericin with Au NPs for 6 h. Scale bar, 20 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.) (Zhu 2024).

To elucidate the mechanism by which Au NPs suppress IL-1β secretion and NLRP3 activation, Zhu et al. investigated the dose–dependent effects of Au NPs ( ≤ 200 μg/mL) on NLRP3 and ASC expression. Their findings revealed that Au NPs suppress inflammasome activation in an NF-κB–independent manner (Figure 13b). Further mechanistic investigations demonstrated that 30 nm Au NPs significantly reduced ROS and mitochondrial stress upon erythromycin stimulation (Figure 13c,d). Co–immunoprecipitation assays showed reduced NLRP3-NEK7 binding following Au NP treatment, while NLRP3-ASC interaction remained unaffected (Figure 13e,f). These findings were further corroborated by proximity ligation assays, confirming that Au NPs selectively disrupt the NLRP3-NEK7 interaction (Figure 13g). In summary, 30 nm Au NPs inhibit NLRP3 inflammasome activation by specifically interfering with NLRP3-NEK7 complex formation, rather than the NLRP3-ASC interaction.

4.2. Targeted inhibition of NLRP3 inflammasome activation via nanoparticle–mediated delivery of inhibitors

Despite the therapeutic potential of NLRP3 inflammasome inhibitors, clinical applications remain limited by a narrow therapeutic window, poor patient tolerance, and physiological barriers such as the blood–brain barrier (BBB) (Tang 2023; Zhao 2024). However, advancements in nanomedicine–particularly in drug delivery, immune modulation, and oxidative stress regulation–have enabled innovative strategies for targeted delivery of NLRP3 inhibitors. Table 1 summarizes recent nanocarrier–based approaches targeting NLRP3 in inflammatory disease therapy.

Table 1.

Functionalized nanoparticles target delivery of NLRP3 inhibitors for the treatment of inflammatory diseases.

Functionalized nanoparticles	Drug	Disease model	Mechanism	Advantages	Reference
mCu–PDA/SOD	polydopamine	PD mouse models	Antioxidation Inhibit the production and activation of NLRP3 inflammasome	Efficiently across the blood–brain barrier to achieve brain aggregation	(Jiang 2025)
M–PMPL@Tf	MCC 950	MCAO rat model	Antioxidation Inhibit the production and activation of NLRP3 inflammasome	pH–dependent drug release	(Prakash 2023)
KM@M@M	MCC 950	murine CaOx nephrocalcinosis model	Antioxidation Inhibition of NLRP 3 inflammasome activation Prevent cell apoptosis	Targeted delivery	(Ba 2025)
GBLA−22/Cas9 RNP	Cas9 ribonucleoprotein	psoriatic mouse model	Inhibition of NLRP 3 inflammasome activation	Efficient delivery	(Tan 2024)
QM@EP	MCC 950	Ulcerative colitis mouse model	Inhibition of NLRP 3 inflammasome activation	Intelligently responding to colonic biomarkers for targeted delivery and release Bioimaging	(Sun et al. 2022)
BHB–dAB	β-hydroxybutyric acid	diabetic rat wound model	Promote macrophage transformation into anti–inflammatory phenotype Mitochondrial protection NLRP 3 inflammasome regulation	Targeting macrophages Lysosomal escape	(Mao 2025)
NR–NLC	Nerolidol	Swiss albino mice	Antioxidation Inhibition of NLRP 3 inflammasome activation Neuroprotection	Efficiently across the blood–brain barrier to achieve brain aggregation	(Iqubal 2020)
MM/ANPs	apelin−13	MCAO rat model	Inhibition of NLRP 3 inflammasome activation	Actively cross the BBB and target the ischemic–inflammatory region	(Ma 2024)
NMM	MCC 950	Myocardial infarction mouse model	Inhibition of NLRP 3 inflammasome activation	Targeted delivery Lysosomal escape	(Cheng 2020)
MN patch	Cas9 ribonucleoprotein dexamethason	AD mouse model	Inhibition of NLRP 3 inflammasome activation	Stepwise delivery strategy Genome editing technology	(Wan et al. 2021)

In terms of delivery system design, nanotechnology has significantly enhanced the therapeutic efficacy of NLRP3 inhibitors. For example, Jiang et al. (2025) developed a multifunctional microgel system based on superoxide dismutase (SOD) and copper ions, which regulates neuroinflammation via the CX3CL1/CX3CR1-NF-κB–NLRP3 signaling pathway in Parkinson’s disease models. This platform not only mimics SOD and catalase (CAT) activity but also promotes neurogenesis and modulates neuroinflammatory signaling (Figure 14a–d).

Figure 14.

(a) Schematic illustrating the preparation process of mCu–PDA/SOD microgel system and its therapeutic mechanisms on PD based on promoting neurogenesis and regulating chemokine axis (CX3CL1/CX3CR1)-mediated communication between neurons and microglia. VIM: vinyl imidazole, APS: ammonium persulphate, DA: dopamine, MPC: 2-methacryloyloxy ethyl phosphorylcholine, PEGMA: poly(ethylene glycol) methyl ether methacrylate, EDGMA: Ethylene dimethacrylate, SOD (db): Superoxide dismutase with double bonds, pS129: serine 129 phosphorylated α-synuclein, TH: tyrosine hydroxylase, GFAP: glial fibrillary acidic protein, Iba−1: ionized calcium–binding adapter molecule−1, ROS: reactive oxygen species. (b) Quantitative results of probe fluorescence intensity and the corresponding fluorescence detection images, n = 3 independent experiments. Data represent the mean ± SD. The scale bar is 50 µm. (c) Immunofluorescence staining of CD206 in BV2 cells. (d) Cell apoptosis detection via immunofluorescence staining of bcl−2 and caspase−3. The scale bar is 50 µm (Jiang 2025).

Similarly, MCC950-loaded PMPL@Tf nanomicelles improve drug stability and biocompatibility while crossing the BBB through transferrin receptor 1 (TFR1)-mediated targeting, achieving neuroprotective anti–inflammatory effects (Prakash 2023). In renal diseases, Kim−1–targeted MCC950-loaded nanoparticles coated with macrophage membranes (KM@M@M) facilitate precise delivery to damaged renal tubules, reducing ROS, NLRP3 activation, GSDMD cleavage, and pro–inflammatory cytokine production–ultimately inhibiting pyroptosis and alleviating kidney stone–induced damage (Ba 2025).

Nanocarriers have demonstrated remarkable promise across diverse inflammatory conditions. For psoriasis, dual–responsive nanoparticles successfully delivered Cas9 ribonucleoprotein complexes targeting NLRP3, effectively disrupting inflammasome formation and alleviating inflammation (Tan 2024). In ulcerative colitis, orally administered nanocarriers (QM@EP) released MCC950 to suppress NLRP3 activation with therapeutic efficacy (Sun et al. 2022). In diabetic wound healing, apoptosis–body–mimicking nanoparticles modified with folate and DSPE–PEG delivered β-hydroxybutyrate (BHB) to inflamed M1 macrophages. By blocking K⁺ efflux and reducing ASC oligomerization and speck formation, these nanoparticles effectively suppressed NLRP3 activation (Figure 15a). Animal studies demonstrated enhanced wound closure in diabetic rats treated with BHB–dAB by day 14, approaching outcomes seen in healthy controls (Figure 15b,c).

Figure 15.

(a) Schematic diagram depicting the preparation of BHB–dABs and their regulation of the Nod–like receptor protein 3 (NLRP3) inflammasome in diabetic wounds. Apoptotic bodies (ABs) were prepared by inducing apoptosis and differential centrifugation of adipose stem cells (ADSCs). Engineered ABs targeted M1 macrophages via ligand–receptor interactions, while lysosomal escape was facilitated by the principle of ‘like dissolves like’. This dual functionality of the ABs enhanced the pharmacological efficacy of β-hydroxybutyric acid (BHB) and promoted diabetic wound healing. BHB–dABs, DSPE–PEG–FA–modified apoptotic bodies loaded with β-hydroxybutyric acid; DSPE, 1,2-distearoyl–sn–propyltriyl−3-phosphatidylethanolamine; PEG, polyethylene glycol; FA, folic acid; STS, staurosporine; ADSC, adipose stem cell; TCA, tricarboxylic acid; ASC, apoptosis–associated speck–like protein containing CARD; NEK−7, NIMA–related kinase 7; GSDMD, gasdermin D; NT, N-terminal fragment; pro–IL-1β, interleukin-1β precursor; IL-1β, interleukin-1β. (b) Typical images and (G and H) statistical analysis of immunofluorescence after treatment with ABs, DP@ABs, FDP@ABs, and BHB–FDP@ABs. *P < 0.05; **P < 0.01; ***P < 0.001. STZ, streptozotocin; DAPI, 4′,6-diamidino−2-phenylindole; DiD, 4′,6-diamidino−2-phenylindole. (c) Representative wound images following treatment with control, phosphate–buffered saline (PBS), BHB, dABs, and BHB–dABs at 0, 3, 7, and 14 d (Mao 2025).

Other innovative nanoplatforms include nerolidol–loaded lipid nanocarriers (NR–NLCs) that modulate oxidative stress, NLRP3, caspase−1, and neurotransmitters to treat cyclophosphamide–induced neuroinflammation (Iqubal 2020); macrophage membrane–encapsulated apelin−13 nanoparticles for ischemic stroke therapy via suppression of NLRP3-mediated pyroptosis (Ma 2024); and enzyme–responsive microspheres that precisely deliver NLRP3 inhibitors to improve post–myocardial infarction cardiac dysfunction (Cheng 2020). Moreover, soluble microneedle patches developed by Wan et al. (Wan et al. 2021) facilitated transdermal delivery of CRISPR–Cas9 and glucocorticoid–loaded nanoparticles, effectively disrupting NLRP3 inflammasomes in subcutaneous cells. In a psoriasis model, these patches significantly alleviated IMQ–induced clinical symptoms and histological abnormalities (Figure 16a–d).

Figure 16.

(a) Schematic illustration of stepwise transdermal and intracellular delivery of genome–editing agents (Cas9) and glucocorticoids (Dex) for the treatment of ISDs. (b) Schematic illustration of dual MN patch for the treatment of imiquimod–induced psoriasis. (c) Photographs of mice treated with various formulations. (d) H&E staining of the skin tissue sections from the mice after the specified treatments (magnification, ×40 and ×100; scale bars, 500 and 200 μm, respectively). For (a) to (d), the code denotes the following: G1, normal mice without imiquimod treatment; G2, imiquimod–treated mice without therapy; G3, imiquimod–treated mice treated with blank MN patch; G4, DNCB–treated mice treated with Dex–loaded MN patch; G5, imiquimod–treated mice treated with RNP–loaded MN patch; G6, imiquimod–treated mice treated with dual–loaded MN patch; G7, imiquimod–treated mice treated with Dex cream; and G8, imiquimod–treated mice treated with tacrolimus ointment (Wan et al. 2021).

In conclusion, nanotechnology–based drug delivery systems offer significant advantages in enhancing NLRP3 inhibitor efficacy by improving drug stability, targeting precision, and biocompatibility. These advances lay a robust foundation for expanding the clinical applicability of NLRP3-targeted therapies and advancing precision medicine in the treatment of inflammatory diseases.

5. Current challenges and future perspectives

Although a growing body of preclinical studies has demonstrated the potential of nanotechnology in targeting the NLRP3 inflammasome for the treatment of various inflammation–related diseases, the clinical translation of such nanotherapeutics remains in its infancy. Nonetheless, emerging clinical studies and translational efforts are gradually bridging the gap between bench and bedside, highlighting the feasibility and promising outlook of NLRP3-targeted nanomedicine in clinical settings. The NLRP3 inflammasome is now recognized as a critical mediator in the pathogenesis of multiple human diseases, including atherosclerosis, type 2 diabetes, Alzheimer’s disease, rheumatoid arthritis, inflammatory bowel disease, and acute organ injuries (Wang et al. 2025). For instance, Ventyx’s VTX−3232 achieved positive topline results in improving Parkinson’s symptoms. It significantly reduced IL-1β and IL−18 levels in both plasma and cerebrospinal fluid, confirming target engagement, and the MDS–UPDRS scores demonstrated statistically significant improvements in both motor and non–motor symptoms in patients with Parkinson’s disease (Ventyx Biosciences 2025).

Traditional small–molecule NLRP3 inhibitors, such as MCC950, have shown favorable therapeutic outcomes in animal models. However, their clinical development is hindered by several challenges, including non–specific targeting, low bioavailability, and potential safety concerns such as hepatotoxicity (Mangan et al. 2018). Nanotechnology offers potential solutions to these issues by enabling targeted delivery, controlled release, and improved pharmacokinetic profiles. These features are expected to significantly enhance the therapeutic index of NLRP3 inhibitors while minimizing systemic toxicity. Although no nanomedicines specifically targeting NLRP3 have yet been approved for clinical use, translational research is actively progressing. For instance, OLT1177 gel (Dapansutrile), a topical selective NLRP3 inhibitor, has entered clinical trials for osteoarthritis and pain management (NCT01768975, NCT02104050, NCT01636141). While nanotechnology has not yet been incorporated into its delivery strategy, nanoformulation approaches are under consideration to further improve its targeting efficiency and bioavailability. In addition to clinical studies, multiple patents have been filed worldwide to protect novel NLRP3 inhibitors, highlighting the pharmaceutical industry’s interest in this therapeutic target and its potential commercial value. For example, Novartis has submitted patents covering MCC950 and its structural analogs for the treatment of various inflammatory diseases (WO/2024/023696). HANGZHOU INNOGATE PHARMA CO., LTD. has also invented novel tricyclic heteroaryl derivatives, along with their synthetic methods, and claimed their application as NLRP3 inhibitors in the preparation of drugs for treating tumors and other related diseases (WO/2022/171185). These patents underscore the dynamic development landscape of NLRP3 inflammasome–targeting agents and further reinforce their relevance for future clinical translation.

Despite the remarkable potential of nanotechnology in treating inflammation–related diseases via NLRP3 inhibition, several obstacles must be overcome before clinical translation. Firstly, the biocompatibility and long–term safety of nanomaterials remain unresolved. Although various materials–including lipids, polymers, and metal oxides–have been extensively investigated in preclinical studies, their long–term toxicity, immunogenicity, and chronic accumulation in human tissues require thorough evaluation, particularly in the context of repeated dosing or chronic disease management. Secondly, the stability, degradation, and metabolic pathways of nanocarriers in vivo are still poorly understood. Nanoparticles are prone to aggregation, protein corona formation, and nonspecific clearance in complex physiological environments, which can reduce targeting efficiency and therapeutic efficacy. Moreover, the degradation rate and byproducts of different materials may elicit undesirable toxicological responses, further restricting clinical application.

In addition, achieving high targeting efficiency and controlled drug release remains a major hurdle. It is critical to ensure the precise accumulation of nanomedicines in specific inflammatory tissues or cells–such as activated macrophages or damaged endothelial cells–while enabling spatiotemporal controlled drug release. To address these challenges, future research should explore the integration of targeting ligands (e.g. antibodies, aptamers, peptides), stimuli–responsive materials (e.g. ROS-, pH-, or enzyme–sensitive systems), and surface modification strategies to improve tissue and cell specificity and reduce systemic toxicity. Moreover, multifunctional nanoplatforms integrating photothermal therapy (PTT), photodynamic therapy (PDT), or magnetically responsive components may provide synergistic therapeutic benefits and enable real–time imaging and monitoring, forming a basis for theranostic (therapy + diagnosis) strategies for NLRP3 modulation. The development of personalized nanotherapeutics–tailored to patient–specific pathological features, biomarkers, and NLRP3 expression levels–also holds great promise in enhancing treatment efficacy and clinical responsiveness. Finally, to accelerate the translation of basic research into clinical applications, interdisciplinary collaboration must be strengthened, and efforts should be made to optimize manufacturing processes, establish comprehensive toxicological assessment protocols, and standardize preclinical evaluation systems. These efforts will be key to overcoming the so–called ‘valley of death’ between laboratory discovery and clinical implementation.

6. Conclusion

The NLRP3 inflammasome plays a central role in the pathogenesis of various inflammation–related diseases and has emerged as a promising therapeutic target. The rapid advancement of nanotechnology offers innovative strategies for modulating the NLRP3 pathway, improving drug targeting and bioavailability, and enhancing therapeutic outcomes through smart responsiveness and synergistic functions. In multiple animal disease models, nanotechnology–based interventions targeting NLRP3 have demonstrated promising results, supporting their potential for future clinical use.

Despite the encouraging progress, significant barriers such as biosafety, targeting precision, and formulation standardization must still be addressed. With continued improvements in nanomaterial design, the development of theranostic platforms, and the implementation of personalized treatment strategies, NLRP3-targeted nanomedicines may represent a new paradigm for the treatment of inflammatory diseases. Ongoing research efforts in both fundamental science and translational medicine will be essential to unlocking the full therapeutic potential of these advanced systems and paving the way for precision treatment of inflammation–related conditions.

Funding Statement

This study was supported by grants from the National Natural Science Foundation of China (Nos. 82002101, 82002096), Natural Science Foundation of Hubei Province (No. 2023AFB825), and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. 2023A15). (Hubei Provincial Natural Science Foundation of China)

Author contributions

Xuan Zhao is the first author and took the lead in writing–original draft and project administration. Zhikai Xu, Dongfang Wang, and Tonghan Li contributed equally to the investigation and writing–original draft. Ligang Xu, Zhanfei Li, Xiangjun Bai, and Hao Zhu assisted in methodology and writing–review & editing. Yukun Liu and Yuchang Wang assisted in funding acquisition, supervision, writing–review & editing and are the corresponding authors. All authors read and approved the final manuscript.

Disclosure statement

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Consent statement

Not applicable. No individual personal data are included in the study.