Inflammation-modulating polymeric nanoparticles: design strategies, mechanisms, and therapeutic applications

Summary

Inflammation plays a pivotal dual role in disease pathogenesis, acting as both a protective response and a critical factor to chronic inflammatory pathologies. Traditional anti-inflammatory therapies remain constrained by adverse effects and suboptimal bioavailability, necessitating innovative therapeutic paradigms. Polymeric nanoparticles (PNPs) have emerged as a promising alternative for inflammation modulation, offering significant drug-loading capacity, precise targeting, biodegradability, and stimuli-responsive properties. This review summarises PNPs as a versatile nanomedicine platform for inflammation modulation. The physiological and pathological mechanisms underlying inflammation are elucidated, followed by a comprehensive summary of the engineering strategies, mechanistic actions, and therapeutic potential of PNPs for inflammation modulation. The clinical translation challenges, including toxicity and off-target effects, are discussed. The potential future directions for multifunctional PNPs in theranostics and AI-driven personalised inflammation modulation are finally proposed. This work seeks to bridge polymeric nanomaterials innovation and precision medicine to drive next-generation anti-inflammatory therapies.

Introduction

Inflammation serves as a fundamental defence mechanism against pathogenic invasion, tissue injury, or xenobiotic exposure, with its physiological progression tightly governed by the spatiotemporally coordinated interplay between the innate and adaptive immune systems to re-established homoeostasis.^1,2 During acute inflammation, neutrophils and monocytes are rapidly recruited to injury sites via chemokine gradients to eliminate pathogens and initiate tissue repair, while specialised pro-resolving lipid mediators (e.g., lipoxins, protectins) orchestrate macrophage phenotype transitions to actively drive inflammatory resolution.³ However, when inflammation becomes chronic due to persistent stimuli or dysregulated immune homoeostasis, excessive production of reactive oxygen species (ROS), proteases, and pro-inflammatory cytokines (e.g., tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β)) disrupts tissue homoeostasis, initiating a pathological cascade.^4,5 This progression ultimately results in irreversible tissue damage and organ dysfunction, serving as a central pathogenic mechanism in autoimmune diseases (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis (RA)), neurodegenerative disorders (e.g., Alzheimer’s disease (AD)).

Conventional anti-inflammatory therapies, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and biologics (e.g., TNF-α inhibitors), provide partial symptomatic relief and are intrinsically limited in their clinical translation. NSAIDs mediate their clinical effects by competitively inhibiting cyclooxygenase (COX) enzymes, which regulate prostaglandin biosynthesis. However, prolonged use is dose-dependently associated with gastrointestinal ulceration, cardiovascular complications, and nephrotoxicity.⁶ Glucocorticoids exert potent immunomodulatory effects via glucocorticoid receptor activation and subsequent transcriptional regulation. However, their broad immunosuppressive activity increases susceptibility to metabolic disorders and infections during long-term therapy.⁷ Despite their pronounced therapeutic efficacy and favourable safety profile, biologics face significant translational challenges, including high production costs, short half-lives, and immunogenicity concerns.⁸ Conventional pharmacological agents lack intrinsic tissue-specific targeting capacity, restricting their ability to precisely modulate inflammatory signalling cascades within complex microenvironments. This limitation compromises the therapeutic efficacy, and is insufficient to halt disease progression. Thus, precision-targeted therapies that resolve pathological inflammation while preserving innate immune defence remain critically needed.

The rapid advancement of nanomedicine has provided unprecedented opportunities for precise inflammation management. By enabling targeted delivery, optimizing pharmacokinetics, and reducing systemic toxicity, nanomedicine has transformed disease treatment paradigms.⁹ In the context of inflammation, nanoplatforms exhibit unique capabilities to overcome biological barriers and evade immune surveillance. This facilitates selective drug accumulation at pathological sites while simultaneously enhancing therapeutic bioavailability and minimizing systemic toxicity.^10,11 Lipid-based and inorganic nanoparticles have demonstrated utility in immunomodulation. For example, lipid-based carriers, such as liposomes, are highly effective at encapsulating hydrophobic drugs and fusing with cell membranes to facilitate cytosolic delivery. However, their structural fragility under physiological shear stress and susceptibility to opsonisation constrain their applicability in chronic inflammatory conditions characterised by prolonged circulatory exposure.¹² Inorganic nanoparticles (e.g., gold, silica) provide enhanced imaging capabilities owing to their intrinsic plasmonic or magnetic properties, yet their non-biodegradable nature raises concerns regarding long-term tissue accumulation and the potential exacerbation of inflammation through oxidative stress amplification.¹³ Notably, polymeric nanoparticles (PNPs) offer distinct advantages and have emerged as versatile nanocarriers. Their tunable physicochemical properties—such as size, surface charge and ligand functionalisation—together with high drug-loading capacity and inherent biocompatibility, render them particularly well-suited to precision inflammation management.¹⁴ Engineered PNPs can exploit pathophysiological features of inflammation, such as vascular hyperpermeability, overexpressed receptors, and dysregulated pH/ROS gradients, to achieve site-specific accumulation. Furthermore, their surfaces can be functionalized with targeting ligands (e.g., antibodies, peptides) or stimuli-responsive moieties to enhance tissue specificity and enable spatiotemporally controlled payload release.¹⁵ In contrast to conventional nanocarriers, biodegradable PNPs are engineered to decompose by enzymatic or hydrolytic cleavage into non-toxic byproducts, thus reducing long-term toxicity risk factors. These attributes establish PNPs as a promising platform for precision anti-inflammatory therapy, bridging the gap between systemic drug delivery and localised therapeutic efficacy.

In this review, we present an overview of recent advancements and innovative strategies in PNPs for inflammation modulation (Fig. 1). First, we delineate key design principles, including material selection, surface modification strategies, and stimuli-responsive release mechanisms. Subsequently, we examine the mechanistic foundations of PNP-mediated inflammatory modulation, focusing on their ability to modulate immune cell phenotypes, suppress pro-inflammatory cytokines, and remodel pathological tissue microenvironments. We then synthesise the therapeutic potential of PNPs across diverse inflammation-related pathologies—including acute injury (e.g., acute lung injury (ALI)), autoimmune disorders (e.g., IBD, RA), and neurodegenerative disease (e.g., AD)—which exemplify distinct immunopathological mechanisms and clinical challenges. Finally, we critically assess translational challenges and propose future research directions to facilitate the transition from preclinical innovation to clinical application.

Fig. 1.

Design strategies, mechanisms, and therapeutic potential of polymeric nanoparticles (PNPs). (a) Design strategies. The design strategies for PNPs include material selection, surface modification, and stimulus-responsive release. PNPs can be fabricated from either natural or synthetic polymers. Surface modification of PNPs is essential for enhancing stability, circulation, targeting, and uptake. Stimulus-responsive release systems in PNPs are diverse, including pH-sensitive, reactive oxygen species (ROS) responsive, and enzyme responsive systems. (b) Mechanisms. PNPs modulate inflammation through multiple mechanisms, including the immune cell modulation, inflammation factors modulation, and oxidative stress modulation. PNPs can modulate immune cell polarisation, such as the M1 to M2 macrophage phenotype transition and the Th17 to Treg cell shift. PNPs can also regulate inflammation by reducing pro-inflammatory factor (e.g., interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) and increasing anti-inflammatory factors (e.g., interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β)). Besides, PNPs can manage oxidative stress through mechanisms such as scavenging ROS and releasing superoxide dismutase (SOD). (c) Therapeutic potential. PNPs currently demonstrate therapeutic potential for diverse inflammation-related diseases, including but not limited to the treatment of Alzheimer’s disease, acute lung injury, inflammatory bowel disease, and rheumatoid arthritis.

Design strategies for inflammation-modulating PNPs

The design of inflammation-modulating PNPs represents a multidisciplinary challenge that integrates materials science, bioengineering, and pharmacology. By leveraging material selection, surface engineering, and smart responsive systems, PNPs address the limitations of conventional anti-inflammatory therapies such as systemic toxicity and insufficient targeting (Table 1). This section systematically evaluates the latest advancements in PNP design strategies for precise inflammation modulation.

Table 1.

Design strategies for inflammation-modulating PNPs.

Strategy	Type	Mechanism	Advantage	Challenge	Reference
Materials selection	Natural polymers	Low immunogenicity and biodegradability	Promotes cell uptake and immune regulation	Limited mechanical strengths	16, 17, 18, 19
	Synthetic polymers	Customizable, adjustable degradation rate	Controllable degradation rate	Adjustable mechanical properties and degradation rates, as well as individual customization	15,20
Targeted modification	Cell membrane	Erythrocyte membrane, macrophage membrane, neutrophil membrane, etc., transmit self-signals to the corresponding cells	Immune escape, prolonging circulation time	The preparation process is complicated and membrane proteins are easily inactivated	21,22
	Glycosylation modification	Sugar molecules (e.g., fucose, beta glucan, sialic acid) bind to cell surface receptors	High chemical stability and low immunogenicity	Carrier-modified sugar molecules may compete with natural sugar molecules in vivo and be degraded by glycosidase, impacting targeting efficiency.	23,24
Stimulus-response release systems	pH responsive	Acidic inflammatory microenvironment triggers material degradation or conformational change	Simple synthesis and wide applicability	Less sensitive in vivo and easily disturbed by physiological environment	25,26
	ROS responsive	Oxidation-sensitive materials (e.g., thioketal, disulphide bond, diselenium bond, phenylborate)	High specificity, synergistic therapy (releasing drugs while clearing ROS), dynamically adjust the release rate in real-time based on changes in inflammation levels.	Long-term stability to be verified	27, 28, 29, 30
	Enzyme response	Inflammatory high-expression enzymes (e.g., MMPs, hyaluronidases) degradable materials	High specificity, controlled release	Individual differences in enzyme concentration	31,32

Materials selection

The choice of polymeric materials dictates the biocompatibility, biodegradability, and therapeutic efficacy of PNPs. Natural and synthetic polymers offer distinct advantages and challenges, requiring rational design to optimise performance.

Natural polymers derived from biological sources (e.g., polysaccharides, proteins), always exhibit excellent biocompatibility and intrinsic biodegradability. Chitosan is a kind of polycationic polysaccharide that promotes electrostatic interactions with negatively charged cell membranes, enhancing cellular uptake. For instance, an antibiofilm drug featuring engineered bioactive chitosan-based nanoparticles (CSNPs) has demonstrated immunomodulatory effects in the treatment of apical periodontitis. The CSNPs are internalised via macropinocytosis, clathrin-mediated endocytosis, and phagocytosis, thereby reprogramming the macrophage proteome and modulating cytokine production to significantly reduce inflammation.¹⁶ In addition to the choice of natural polymers, molecular weight of polysaccharides also affects the regulation of inflammation.^17,18 Humayune et al. studied the immunomodulatory activity of galactoglycan (funoran and furcellaran) and its partial depolymerised derivatives on macrophages RAW264.7, and found that the molecular weight of polysaccharide plays a key role in the immune response of RAW264.7.¹⁷ Galactans with high molecular weight may induce macrophages to secrete more pro-inflammatory cytokines (such as TNF-α, IL-1β, etc.), and enhance the immune inflammatory response in response to potential pathogen invasion. Low molecular weight derivatives may induce macrophages to secrete anti-inflammatory cytokines (such as IL-10, etc.), which help control the degree of inflammatory response and prevent excessive immune damage. However, the mechanical strength and function of natural polymers are limited, and the required function cannot be introduced to the main chain structure.

Recently, synthetic polymers have received a lot of attention due to their customisability and versatility. Poly(lactide-co-glycolid) (PLGA), an FDA-approved biodegradable polymer, offers tunable degradation rates through adjustment of the lactic acid (LA) to glycolic acid (GA) ratio. For instance, 50:50 PLGA degrades within one to two weeks.²⁰ Methotrexate-loaded PLGA nanoparticles decrease joint inflammation in rheumatoid arthritis models by inhibiting Th17 cell differentiation. Due to its inability to mimic biological substances, pure PLGA is readily cleared by the immune system, thereby limiting its duration of action within the body. Thus, PEGylation or biomimetic coating is a common strategy to improve the biocompatibility of synthetic polymer nanoparticles. Polyethylene glycol (PEG) coatings (e.g., PEG-PLGA) extend blood circulation time (>24 h) by minimizing macrophage uptake. Combining PEG with targeting peptides (e.g., RGD) enhances endothelial cell targeting in inflamed tissues.¹⁵ Moreover, through introducing stimulus-responsive groups or biomimetic modifications, nanoparticles can be endowed with specific response capabilities to the inflammatory microenvironment (such as ROS, pH value, enzyme concentration, etc.), thereby achieving precise drug release and inflammation regulation.^33,34 Wang et al. designed and synthesized zwitterionic polyurethanes containing thioketal diamine structures. These nanoparticles have the ability to selectively enhance the expression of H₂O₂ while inhibiting other types of ROS.³⁵ Zhao et al. reported a reversible phenylborate ester with a large molecule prodrug (PBC) containing caffeic acid (CA), which was loaded into the balloon catheter coating, aiming to release CA and 4-hydroxybenzyl alcohol triggered by local high levels of ROS, and exert efficient antioxidant and anti-inflammatory effects by eliminating ROS.³⁶

The preparation strategy for polymer nanoparticles is critical to their performance and application, complementing material selection. Currently, preparation methods are primarily categorised into physical, chemical, and biological approaches. Physical methods, including nano-precipitation and spray drying, are straightforward and scalable but offer limited control over particle size.^37,38 Chemical methods, such as emulsion and interfacial polymerisation, allow precise control of particle size and morphology through reaction condition adjustments, and can impart special functionalities to the particles.³⁹ However, residual chemical reagents may pose biological safety concerns. Active/controlled free radical polymerisation can produce nanoparticles with regular structures and good monodispersity, suitable for designing intelligent responsive materials.⁴⁰ Notably, microfluidic technology, a cutting-edge method, can achieve high-throughput and monodisperse nanoparticle preparation by precisely controlling fluid parameters, and can accurately regulate particle composition and structure.⁴¹ This technology is expected to facilitate the transition of polymer nanoparticles from laboratory research to industrial application. As preparation technologies continue to innovate and integrate across disciplines, polymer nanoparticles will likely expand their application prospects in biomedical fields.

Targeted modification

While passive targeting via the enhanced permeability and retention (EPR) effect relies on leaky vasculature, active targeting strategies improve specificity by incorporating ligands or bio-inspired coatings.

Cell membrane-encapsulated nanoparticles (e.g., erythrocyte membrane, macrophage membrane) mimic the “self” recognition signal of native cells through the surface glycoprotein and lipid bilayer structure, significantly reducing the clearance of core solo macrophage system.²¹ Targeted peptides or antibody fragments regulate the surface properties of PNPs, reduce specific adsorption, and enhance inflammatory cell recognition. In addition, binding PNPs to liposomes mimicking the surface of macrophages, or expressing macrophage surface markers (e.g., CD47) through genetic engineering, inhibits the phagocytosis of core solo cells and prolongs the cycle time. However, the membrane protein is more prone to inactivation during the preparation process (such as the loss of immune escape function due to the conformational change of CD47).²² Besides, the cell membrane components are vulnerable to oxidative stress and pose long-term stability risks. Therefore, glycosylation targeting strategies become an alternative option through the interaction of sugar molecules (such as sialic acid, fucose, etc.) and cell membrane surface receptors.^23,42,43 In addition, glycosylation can be modified by chemical synthesis, and the sugar chain has good chemical stability. By virtue of the high affinity between fucoidan and thrombosis biomarker P-selectin, de La Taill et al. reported a fucoidan-modified nanoparticle as an effective drug delivery strategy for thrombolytic therapy.²³ β-glucans (β-Glus) can mediate the interaction with inflammation-activated endogenous macrophages, achieving targeted treatment for bacterial meningitis. Nguyen et al. proposed the preparation of nanoparticles (β-Glus-CTX NP) by combining naturally derived β-Glus and the antibiotic cefotaxime (CTX) using a ROS-responsive linker.²⁴ And the bionic delivery strategy was used to realise the efficient targeted treatment of meningitis by utilizing the natural migration ability of endogenous macrophages and the responsive drug release mechanism of the inflammatory microenvironment.

Stimulus-responsive release systems

Inflammatory microenvironments, characterised by their distinct biochemical signatures, offer a unique platform for the development of precision medicine. These microenvironments, which are present in various pathological conditions such as cancer, autoimmune diseases, and chronic infections, are replete with specific triggers such as pH changes, ROS, and enzymatic activities.³⁴ These triggers, hitherto considered mere byproducts of inflammation, now emerge as valuable cues for the spatiotemporal control of drug activation. By harnessing these triggers, researchers can design drug delivery systems that respond exclusively to the inflammatory milieu, thereby ensuring controlled drug release precisely where and when it is needed most. The pH of inflammatory microenvironments often deviates significantly from the physiological norm, creating an acidic niche that can be exploited for pH-sensitive drug release. For instance, certain polymeric drug carriers can be designed to degrade or release their payloads only in the presence of such low pH values, thus ensuring that the drug is activated only at the site of inflammation (Table 2).^25,26 This not only enhances the therapeutic efficacy by targeting the drug directly to the diseased tissue but also reduces systemic side effects associated with traditional drug delivery methods. ROS can also be exploited for controlled drug release. ROS-responsive drug delivery systems, equipped with redox-sensitive linkages (e.g., thioketal, diselenyl bond, disulphide bond and phenyl borate) or materials, can disintegrate or release their therapeutic cargos in response to elevated ROS levels present in inflammatory microenvironments (Table 2).27, 28, 29, 30 This strategy not only ensures site-specific drug delivery but also potentially amplifies the therapeutic effect by harnessing the inherent oxidative stress of the inflamed tissue. Moreover, enzyme-sensitive drug delivery systems, armed with specific cleavable linkages or prodrugs, can be designed to release their active components only in the presence of the target enzyme.^31,32 Matrix metalloproteinase 9 (MMP9)-lysable methoxy-containing polyethylene glycol can be co-conjugated with therapeutic agents to form prodrugs that enhance its accumulation in diseased tissues when exposed to MMP9 overexpression.³² This approach not only ensures selective drug activation but also provides a means to monitor and regulate the therapeutic response by modulating the enzymatic milieu.

Table 2.

Types of chemical bonds and response characteristics.

Types	Related chemical bonds	Response characteristics
pH responsive44	Hydrazone bond (-N=N-)	It is easily hydrolysed under acidic conditions and stable under alkaline conditions.
	Ketal bond (-C-O-C-)	Acid-sensitive, rapidly hydrolyses to form aldehydes/ketones and alcohols under acidic conditions.
	Carboxylate ester bond (-COO-)	It hydrolyses slowly under weakly acidic conditions, and the hydrolysis is accelerated under strongly acidic or alkaline conditions.
ROS responsive44,45	Thioether bond (-R-S-R'-)	Highly sensitive to H2O2 (1–10 mM), but less sensitive to O2·- and ·OH.
	disulphide (-R-S-S-R'-)	Dual responses: H2O2 (oxidation) and GSH (reduction).
	Boronate (-B(OR)2)	It only has a specific response to H2O2 and is not sensitive to other ROS.
	Selenide (-R-Se-R'-)	It is sensitive to both H2O2 and ·OH, and catalytically scavenges ROS.
	Thioacetal (-C(SR)2-)	Specifically responsive to H2O2, and the hydrolysis is accelerated after oxidation.
	Peroxo-linkage (-R-O-O-R'-)	Sensitive to various ROS (H2O2, O2·-, ·OH).
	Thioketone (-C=S-)	Selectively responsive to H2O2.

The future development of inflammatory regulation PNPs will show the trend of intelligent materials, precise targeting, and systematic delivery. By integrating biomimetic materials, intelligent response mechanisms and combined treatment strategies, such PNPs are expected to achieve breakthroughs in the treatment of inflammatory diseases (such as arthritis, inflammatory bowel disease, and neuroinflammation), providing safer and more efficient treatment options for clinical application.

Mechanisms of inflammation-modulating PNPs

PNPs offer an innovative approach to the accurate control of inflammation because of their multi-mechanism synergistic effects, intelligent response capabilities, and designable physiochemical characteristics. PNPs can dynamically repair the inflammatory microenvironment from the molecular to the organelle levels by combining the three synergistic pathways of immune regulation, cytokine intervention, and redox balance (Fig. 2).

Fig. 2.

Mechanisms of inflammation-modulating PNPs. (a) Mechanisms of modulation of intrinsic immune cells (macrophages) and adaptive immune cells (T lymphocytes) by PNPs. (b) Mechanisms of modulation of inflammatory factors by PNPs, including direct blockade of immune storm and modulation of inflammatory factor secretion by immune cells. Antibodies and inhibitors are commonly used to directly block the immune factor storm, while siRNAs and CRISPR systems are typically used to regulate the expression of inflammatory factors. (c) Regulatory mechanisms of PNPs on oxidative stress, which includes transient scavenging of free radicals, sustained regeneration of enzyme systems, and mitochondrial homoeostatic protection.

Immune cell modulation

The modulation of the immune system by PNPs begins with targeted intervention on intrinsic immune cells. The inflammatory cascade response is triggered in the early stages of inflammation by the overactivation of M1-type macrophages, which produce a lot of pro-inflammatory chemicals (e.g., TNF-α, IL-6).⁴⁶ Research has demonstrated that surface-modified hydrolysed galactomannan (hGM) PNPs can target macrophages through lectin-like receptors on the cell membrane, which are endocytosed by clathrin- and caveolin-dependent pathways within 1 h, causing M2 polarisation and M1-to-M2 switching as well as the induction of anti-inflammatory markers such as arginase-1 (Arg-1).⁴⁷ PNPs loaded with 18β-glycyrrhetinic acid inhibit the intracellular translocation of HMGB1 in the nucleus, reducing the promotion of HMGB1 to downstream cells and realising the dynamic transition of microglia phenotype from M1-type to M2-type.⁴⁸ Co-encapsulating curcumin (Cur) and poly (−)-epigallocatechin-3-gallate (pEGCG) in hyaluronic acid (HA), PNPs not only prevents apoptosis but also regulates CD74 and promotes microglial polarisation to the M2 phenotype, thereby inhibiting inflammatory responses and promoting neuronal regeneration.⁴⁹ In adaptive immune regulation, T cell subset imbalance (e.g., Th1/Th17 overactivation against Treg function suppression) is an important mechanism in a variety of autoimmune diseases. PNPs exhibit spatiotemporal specificity in the regulation of T cell subset homoeostasis. PNPs loaded with rapamycin and autoantigens promote Treg production and inhibit the expression of IFN-γ and IL-6 and promote IL-10 secretion.⁵⁰ PLGA-based PNPs induce abundant TGF-β, IL-4, and IL-10 production by selectively delivering mouse allergen, ovalbumin (OVA), to the liver, which significantly inhibited anti-OVA IgE responses, airway eosinophilia, and Th2 cytokine production in bronchoalveolar lavage fluid.⁵¹ In contrast, dopamine self-polymerising PNPs can act as a direct immunosuppressant to activate Treg cells while directly inhibiting Th cells, including Th1, Th2, and Th17 cells.⁵² In addition, PNPs exert multifaceted immunomodulatory effects: they promote antigen uptake and activate the maturation of dendritic cells (DCs)⁵³; modulate B cell hyperactivation via targeted mRNA delivery to mitigate autoimmune diseases⁵⁴; and enhance the immunocompetence of natural killer (NK) cells by downregulating inhibitory receptor expression.⁵⁵

Inflammatory factor modulation

Chronic inflammation is frequently accompanied by uncontrolled cytokine networks, leading to an “inflammation-injury-reinflammation” cycle. PNPs can interfere in the cytokine storm at several levels by delivering small-molecule inhibitors, antibodies, or gene editing tools. Melatonin-loaded PNPs reduce TGF-β expression by inhibiting activating transcription factor 6 (ATF6), reducing endoplasmic reticulum oxidative stress in hepatocytes.⁵⁶ Similarly, RU.521 and H-151-loaded PNPs reduce IFN-I production and prevent cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)-driven polarisation toward an M1-like phenotype.⁵⁷ In the treatment of intestinal inflammation, PNPs encapsulating monoclonal antibodies against TNF-α break through the gastric acid barrier via an oral delivery system and protect the antibodies from degradation, allowing them to effectively neutralise TNF-α locally in the intestinal tract and significantly reduce pro-inflammatory factor levels, while avoiding systemic immunosuppression as a side effect.⁵⁸ In addition, the introduction of gene silencing technology has further expanded the intervention dimension of PNPs. PNPs loaded with interfering RNAs such as TGF-β1 siRNA, TNF-α siRNA, p65 siRNA, etc., provide an effective anti-inflammatory strategy by directly reducing the expression of inflammatory cytokines. PNPs have also been used to deliver the CRISPR-Cas system for inflammatory therapy, which is a gene editing technology made up of effector proteins and guide RNAs that can control protein production through precise gene editing. PEG-b-PLGA-based cation-assisted lipid nanoparticles effectively disrupted the NE gene in neutrophils by delivering the CRISPR-Cas9 system targeting neutrophil elastase (NE) via intravenous injection, and they reduced insulin resistance in T2D mice by reducing inflammation in the epididymal white adipose tissue (eWAT) and liver.⁵⁹ With the assistance of soluble microneedles, PNPs containing the CRISPR-Cas9 system targeting NLRP3 and dexamethasone (Dex) could be rapidly released and internalised by keratinocytes and peripheral immune cells after transdermal delivery, alleviating skin inflammation by destroying NLRP3 inflammatory vesicles.⁶⁰ By reducing off-target risk through spatiotemporal selective delivery, the synergistic application of these techniques not only overcomes the single pathway constraint of conventional medicines, but also highlights the special benefits of PNPs in complicated inflammatory management.

Oxidative stress modulation

Oxidative stress and inflammation are closely regulated in a bidirectional manner, and PNPs can realise the whole chain of protection from free radical neutralisation to organelle repair through the construction of a targeted elimination antioxidant system. Polyphenol-modified PNPs containing resveratrol can directly neutralise excess ROS in cardiomyocytes via the electron transfer capacity of phenolic hydroxyl groups, thus reducing myocardial inflammation and apoptosis.²⁸ Smart-responsive design further enhances the precision of intervention: pH-sensitive PNPs sense the acidic character of the inflammatory microenvironment, triggering the targeted release of superoxide dismutase (SOD), which results in a significant enhancement of localised SOD activity in the lesion.⁶¹ At the organelle level, mitochondria-targeted PNPs are able to break through biological barriers to precisely deliver manganese dioxide nanoparticles and S-methylisothiourea, which can achieve source inhibition of ROS generation by scavenging abnormal mitochondrial reactive oxygen species (mtROS).⁶² This multi cascade mechanism, which includes transient scavenging of free radicals, sustained regeneration of enzyme systems, and mitochondrial homoeostatic protection, not only breaks the vicious cycle of oxidative stress and inflammation, but also reduces therapeutic side effects by lowering systemic antioxidant depletion. PNPs’ intelligent design allows them to dynamically modify antioxidant tactics based on the needs of various disease microenvironments such as focusing on free radical scavenging in ischaemia/reperfusion injury. In neurodegenerative disorders, PNPs prioritise mitochondrial function repair, suggesting significant adaptability and therapeutic translational promise.

Overall, the synergistic effect of multiple mechanisms of PNPs enables them to exhibit unique advantages in inflammation regulation, including dose-dependent, spatiotemporal specificity, and dynamic homoeostasis regulation. The interaction mode of PNPs with immune cells can be further optimised by modulating their surface topology or introducing modular functional units (e.g., stimulus-responsive “nanoswitches”). With the development of single-cell sequencing and artificial intelligence prediction technologies, the therapeutic model of PNPs is moving towards individualised precision therapy.

Therapeutic applications

PNPs have revealed remarkable potential in the theranostics of a wide range of inflammation-related diseases (Fig. 3). This section will succinctly examine the use of PNPs in many therapeutic domains, such as ALI, IBD, RA, and AD, which collectively encompass a range of inflammation-related pathologies, including acute injury, autoimmune disorders, and neurodegeneration.

Fig. 3.

Therapeutic applications of inflammation-modulating PNPs. Schematic representation of PNPs for the treatment of various inflammatory diseases, including (a) acute lung injury (ALI), (b) Alzheimer’s disease (AD), (c) inflammatory bowel disease (IBD), and (d) rheumatoid arthritis (RA).

Acute lung injury (ALI)

Pneumonia affects the lower respiratory tract of pulmonary parenchyma and is frequently induced by infectious agents such as bacteria, viruses and fungi.⁶³ To mitigate pneumonia, several efficient therapies, including multiple classes of antibiotics and vaccines, have been established but are constrained by challenges in administration. The administration of PNPs to areas of inflammation has lately emerged as a viable strategy.⁶⁴ PNPs containing anti-inflammatory drugs, peptides, and proteins have been used to target macrophages, dendritic cells, and B cells to mitigate inflammation. Furthermore, PNPs may target immune cells and enhance the biological response at the inflammation site.⁶³

Recent investigations have focused on ROS-responsive polymer-carriers due to their chemical linkages being susceptible to breakdown or oxidation into a hydrophilic phase, facilitating accelerated drug release. Thioketal groups exhibit high ROS sensitivity, undergoing rapid oxidative cleavage upon ROS exposure.⁶⁹ For example, Xie et al. synthesised a ROS-responsive polyurethane termed PFTU from poly(propylene fumarate), poly(thioketal), and 1,6-hexamethylene diisocyanate, then chain-extended with a ROS-cleavable thioketal diamine.⁷⁰ PFTU polymer was subsequently used as a crucial element in creating nanoparticles to encapsulate the anti-inflammatory drug dexamethasone, aimed at scavenging free radicals and modulating the microenvironment of ALI (Fig. 4a).⁶⁵ PFTU exhibited rapid release of dexamethasone and effectively scavenged free radicals in both in vitro and in vivo conditions. The PFTU-based NPs mitigated the cytokines (pro-inflammatory), polarised M1 macrophages to M2, reduced apoptosis, and eventually diminished inflammation in the ALI microenvironment. Furthermore, Wang et al. synthesized a ROS-responsive zwitterionic polyurethane to fabricate nanoparticles encapsulating Pazopanib (Pazo). The resultant nanosystem selectively elevated H₂O₂ levels, suppressed other ROS, prolonged lung retention, and reduced TNF-α, IL-1β, and IL-6 levels.³⁵ Moreover, it decreased lung epithelial permeability and pulmonary oedema, thereby modulating the ALI milieu in an LPS-induced mouse model, suggesting its potential as an anti-inflammatory therapeutic platform.

Fig. 4.

The therapeutic mechanisms of inflammation-regulating PNPs. (a) PFTU@DEX NPs were prepared by a modified emulsification method, and these NPs were delivered to the lungs by nebulisation via tracheal intubation. DEX was released faster when exposed to excess ROS, thus modulating the LPS-induced microenvironment of ALI, leading to better treatment of ALI. Reproduced with permission.⁶⁵ Copyright (2022) with permission from Elsevier. (b) Schematic diagram of functionalised gold nanocages (AuNC) preparation [AuNC: PVP-coated AuNC; FA-AuNCs: folic acid (FA)- PEG-coated AuNCs; MP-AuNCs: FA-AuNCs loaded with methylprednisolone (MP); IL-4- AuNCs: MP-AuNCs grafted with IL-4], and intra-articular cavity injection of IL-4@AuNC targeting activated macrophage folate receptor (FR) for the diagnosis and treatment of RA by releasing MP and recombinant IL-4 proteins. Reproduced with permission.⁶⁶ Copyright (2022) with permission from Elsevier. (c) Microgels containing urolithin A (UA) nanogels and calcium ion crosslinked alginate. The microgels were orally administered to reach the site of inflammation and released probes and UA in response to ROS to improve inflammation and regulate the colonic microenvironment. Reproduced with permission.⁶⁷ Copyright (2025) with permission from Elsevier. (d) The nanoparticles were constructed from a PLGA-PEG backbone loaded with fingolimod (FTY) and externally modified with mannose for multi-targeted treatment of AD in conjunction with glycaemic control strategies. Reproduced with permission.⁶⁸ Copyright 2024, American Chemical Society.

Rheumatoid arthritis (RA)

Current RA therapies by using NSAIDs, glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics primarily relieve symptoms via immunosuppression or inhibition of inflammatory mediators, yet they often incur severe side effects that limit long-term efficacy or necessitate high doses. Recently, innovative multifunctional polymeric nanocarriers with transformable characteristics have been developed to facilitate intelligent drug delivery and enhance RA treatment efficacy.⁷¹ The majority of small molecule pharmaceuticals employed in the treatment of RA are hydrophobic. Consequently, micelles with a hydrophobic core are frequently utilised to solubilise and deliver hydrophobic medications. For instance, Wang et al. showed that dexamethasone-loaded poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG) micelles could effectively lower the joint swelling and bone loss in arthritic rats at a low dexamethasone dose, without any unwanted effects.⁷²

Timely identification and intervention of RA are crucial for attaining optimal therapy results. NIR-II photoacoustic molecular imaging is developed as a viable technique for the effective diagnosis and therapy guiding of RA due to its excellent sensitivity and specificity at significant penetration depths. Chen et al. developed a NIR-II polymer nanoprobe conjugated with RA targeted mono-clonal antibody (tocilizumab) termed TCZ-PNPs for theragnostic purposes.²⁰ TCZ-PNPs exhibited exceptional stability, biocompatibility, and photoacoustic properties, facilitating deep-tissue imaging. Their high inflammation specificity enables early RA detection and offers significant therapeutic efficacy compared to free monoclonal antibodies.

Cell-free DNA (cfDNA) originating from apoptotic or necrotic cells, erythroid precursors, mitochondrial DNA, and neutrophil extracellular traps, is implicated in the pathogenesis of RA.⁷³ Its markedly elevated concentration in synovial fluid compared to plasma underscores its potential as a diagnostic biomarker for RA. Cationic polymers NPs may have the potential to neutralise cfDNA to mitigate inflammation in RA.⁷⁴ Liang et al. prepared cationic NPs based on a di-block copolymer of PLGA and poly(2-(diethylamino)ethyl methacrylate) (PDMA) intending to suppress cfDNA activation and relieve RA symptoms.⁷⁵ Our team created a cationic hydrogel containing anti-IL-17A nanobodies that synergistically attenuated the inflammatory activity of neutrophils and alleviated inflammation in RA. The Nbs-containing hydrogel continuously adsorbs cfDNA and slowly releases anti-IL-17A Nbs, which synergistically attenuates neutrophil inflammatory activity by inhibiting IL-17A-stimulated neutrophil extracellular traps (NETs) in neutrophils from arthritic mice, decreasing levels of pro-inflammatory cytokines and suppressing the inflammatory phenotype of neutrophils in vitro.⁷⁶ In addition, by encapsulating the anti-inflammatory drug methylprednisolone (MP) with contrast agents for photoacoustic (PA) phantom and CT imaging in gold nanocages (AuNCs), our team was able to effectively polarise macrophages towards an M2 phenotype and significantly reduce inflammation by targeting M1 and IL-4 with these PNPs (Fig. 4b).⁶⁶ Overall, with the development of biomaterials science, the role of biomaterials, especially inflammation-modulating PNPs, in RA treatment has evolved from pure drug delivery systems to therapeutic microenvironmental modulators, which provide drug-independent therapeutic strategies for rheumatoid arthritis.⁷⁷

Inflammatory bowel disease (IBD)

Substantial attempts have been made to reduce the incidence of IBD, which is rising worldwide. Individuals with IBD have abdominal pain, diarrhoea, and fatigue. Their gastrointestinal tracts often exhibit a disruption of inflammatory homoeostasis, a compromise of the intestinal epithelial barrier, and an accumulation of ROS. The optimal treatment for IBD is oral administration, characterised by high patient adherence, ease of self-administration, excellent safety profile, and cost-effective production. Oral IBD treatment allows drugs to directly target the intestinal mucosa, in contrast to intravenous injection.⁷⁸ Recent studies indicate that prolonged drug-release formulations such as capsules, tablets, and pellets may substantially elevate medicine concentrations in inflamed intestinal areas, enhancing therapeutic effectiveness.⁷⁹ PNPs have emerged as promising vehicles for drug delivery due to their unique advantages, including improved drug solubility, extended intestinal retention time, increased drug accumulation at inflamed sites, and the ability to target specific cells or organelles for drug delivery.^14,80

The superoxide anion is a critical form of upstream ROS and is a pro-inflammatory signal to colonic epithelial and immunological cells. Superoxide anions have a limited lifetime and may vanish during tissue preparation and analysis. Therefore, tissue slices and homogenates cannot accurately count them. There is an immediate need for an oral platform that integrates in situ monitoring of superoxide anions with accurate therapeutic action. To resolve these challenges, Jin et al. developed a ROS-responsive nanogel platform using hyperbranched polymers (HBPAK) to crosslink methacrylate hyaluronic acid (HA-MA) and encapsulate urolithin A as the therapeutic drug (Fig. 4c).⁶⁷ HA-MA functioned as both the nanogel framework and a CD44-targeting component. Additionally, microgels incorporating superoxide anion-specific probes were fabricated via electrospray into calcium ions. This system effectively scavenged ROS, preserved mitochondrial membrane potential, reduced inflammation, promoted colonic epithelial repair, and improved gut microbiota and tight junction integrity.

Research is currently focusing on using PNPs to advance innovative oral drug delivery systems, whereby pH, enzymes, or ROS primarily initiate the release of drugs in the gastrointestinal tract.^81,82 Moreover, many sophisticated sensing methods based on nanotechnology, including surface-enhanced Raman spectroscopy, localised surface plasmon resonance, and PNPs-enabled potentiometric or amperometric sensors, may be used to early identify IBD symptoms.⁸³

Alzheimer’s disease (AD)

AD, the primary cause of dementia, is the most prevalent neurodegenerative disorder, characterised by increasing memory loss, cognitive impairment, and significant deterioration of intellectual abilities.⁸⁴ The fundamental pathophysiology encompasses blood-brain barrier permeability, heightened inflammatory response, ROS accumulation, insufficiency of acetylcholine, absence of neurotrophic factors, and hereditary susceptibility. The complex causes of disease and the blood-brain barrier hinder the absorption of drugs in the brain, which makes treatment challenging.⁸⁵ The systemic injection of medicines may induce significant peripheral side effects, which further restrict the therapeutic options for AD. Extensive studies have been conducted on PNP-based medication delivery to the central nervous system via the intranasal route in AD.⁸⁶ For example, in rats given galantamine hydrobromide chitosan complex NPs intranasally, the particles were found within neurons and showed no toxicity. Brain acetylcholinesterase protein levels and activity were significantly lower in the NPs group than in oral and nasal galantamine hydrobromide solutions.⁸⁷ PEG-PLA NPs were popular carriers because of their safety and clinical translation. PEG-PLA NPs encapsulated α-mangostin successfully mitigated neuroinflammatory responses, improved brain clearance of Aβ, and enhanced drug biodistribution in the brain.⁸⁸

The objective of using biodegradable PLGA NPs for treating AD is attributed to their capacity to permeate the blood-brain barrier and their neuroprotective properties. The hydrophilicity and electronegativity of PNPs facilitated their penetration of the mucus barrier, while mannose ligands conferred nanoparticle IEB targeting ability. Released FTY modulated the polarity of microglia from pro-inflammatory M1 to anti-inflammatory M2 and normalised activated astrocytes, enhancing the clearance of the toxic protein amyloid β (Aβ), while attenuating oxidative stress and neuroinflammation (Fig. 4d).⁶⁸ Curcumin-loaded PLGA NPs administered intravenously to rat brain regions promoted neurogenesis by activating the Wnt/catenin pathway, thereby enhancing in vitro cell proliferation and the expression of brain development-associated genes.⁸⁹ Moreover, these nanoparticles ameliorated learning and memory deficits in amyloid beta-producing rats, suggesting their potential to enhance the brain’s intrinsic regenerative capacity as a therapeutic strategy for AD.

Challenges

Early-phase clinical trials of PNPs demonstrate emerging translational potential. For instance, antibiotic-containing PLGA nanoparticles for the treatment of recurrent pulpal infections provide a new tool for pulpal infection treatment by utilising electrostatic action and sustained drug release to achieve sustained antimicrobial activity and inhibit biofilm formation (ClinicalTrials.gov ID: NCT05442736). Similarly, hyaluronic acid nanoparticles serve as a new nanodermatological tool in periocular regeneration to reshape tear trough deformities in a safe, effective and less invasive manner (ClinicalTrials.gov ID: NCT05742399). Despite significant progress in developing PNPs for inflammation modulation, several critical challenges hinder their clinical translation. A major challenge lies in the long-term biocompatibility and potential cytotoxicity of PNPs, particularly upon prolonged exposure. While PNPs exhibit lower immunogenicity than lipid-based carriers or viral vectors, the impact of their degradation byproducts and cumulative effects in chronic inflammatory conditions remains inadequately understood. For example, acidic degradation byproducts of PLGA may inadvertently activate inflammatory cascades in chronic pathological microenvironments, potentially exacerbating localised inflammation in vulnerable tissues.^90,91 Furthermore, the immunological recognition of polymeric carriers can trigger immune responses via anti-polymer antibody production or complement activation. For instance, repeated administration of PEGylated nanoparticles has been shown to elicit anti-PEG immune responses, leading to accelerated blood clearance and diminished therapeutic efficacy due to the generation of anti-PEG antibodies.^92,93 This immunogenic cascade imposes significant constraints on the long-term stability of PNPs pharmacokinetics and pharmacodynamics in chronic therapeutic regimens.

Off-target effects remain a critical challenge in nanotherapeutic delivery. Despite targeted surface modifications with ligands such as antibodies or peptides, non-specific uptake by the mononuclear phagocyte system (MPS) and off-target accumulation in organs such as the liver and spleen not only diminish therapeutic bioavailability at inflammatory sites but also heighten systemic toxicity risks. The complex molecular pathways underlying inflammatory pathophysiology demand tailored engineering strategies to achieve spatiotemporal control over therapeutic delivery while ensuring biocompatibility. Translational challenges are further exacerbated by the pathological heterogeneity of inflammatory disorders, necessitating precisely tunable, patient-specific therapeutic properties in designing inflammation-modulating PNPs.

The manufacturing scale-up and production reproducibility of PNPs with precisely defined physiochemical characteristics remain major technical challenges. The therapeutic efficacy and biological performance of PNPs critically depend on the stringent control of polymer molecular weight distribution, colloidal stability, and surface functionality. Even slight batch-to-batch variations in these parameters can markedly impact nanoparticle biodistribution and compromise pharmacological outcomes. Furthermore, the absence of standardised preclinical models that faithfully recapitulate human pathophysiology poses significant challenges in assessing therapeutic efficacy and safety. This limitation is exacerbated by the poor translational relevance of murine models, which fail to reflect the complexity of human immune networks, including disease-specific heterogeneity, spatiotemporal cytokine dynamics, and functionally distinct immune cell subsets.

Collectively, overcoming these complex challenges is imperative to enable the clinical translation of PNPs, which necessitates interdisciplinary innovation in precision inflammation modulation.

Conclusions

Inflammation remains a double-edged sword in disease progression, highlighting the urgent need for therapeutic strategies that precisely balance immune activation and resolution. PNPs offer a promising strategy to overcome the limitations of conventional anti-inflammatory therapies, owing to their tunable physiochemical properties, high drug-loading capacity, targeted delivery, and responsiveness to pathological stimuli. This review outlines the design strategies, mechanistic actions, and therapeutic potential of PNPs in various inflammation-related diseases. Although preclinical outcomes are encouraging, significant translational challenges including safety concerns, off-target effects, and manufacturing complexities persist. Collaborative, interdisciplinary innovation will be critical to overcoming current challenges and realising the clinical translation of PNP-based nanomedicine.

Outstanding questions

Next-generation inflammation-modulating PNPs will necessitate a multidisciplinary approach to address biological and technical challenges. First, concerns about the long-term biocompatibility and potential cytotoxicity of PNPs must be addressed. This includes comprehensive toxicological evaluation of currently used polymers over extended periods, as well as the development of novel or chemically modified polymers. Second, repeated administration of PEGylated nanoparticles has been shown to induce anti-PEG antibodies, leading to accelerated blood clearance and diminished therapeutic efficacy. To overcome this immunogenicity, it is crucial to develop alternative surface modification strategies. Promising approaches include the use of next-generation “stealth” polymers, such as zwitterionic materials or poly(2-oxazoline), alongside the refinement of dosing regimens in clinical practise to reduce immune activation. Third, the integration of multimodal targeting mechanisms represents a promising strategy to enhance targeting specificity. By synergistically combining active targeting ligands with stimuli-responsive polymers, this approach enables precise spatiotemporal modulation of PNPs accumulation in inflamed tissues while maintaining optimal adaptability to the dynamic inflammatory microenvironment. In addition, the integration of diagnostic modalities (e.g., imaging agents or biosensors) into PNP-based therapeutic platforms facilitates concurrent therapeutic delivery and real-time monitoring of inflammatory dynamics. Fourth, AI and machine learning (ML) methodologies have emerged as transformative tools in precision medicine for inflammatory disorders. AI-driven frameworks are poised to revolutionise PNP design by enabling high-throughput polymer screening, predicting structure-activity relationships, and optimising drug release kinetics. ML-driven analysis of multi-omics datasets offers a transformative framework for developing precision-engineered PNP therapies customised to patient-specific immunogenetic profiles. Advances in synthesis protocols, the adoption of standardised polymeric materials, and the integration of automated microfluidic platforms with AI-driven process optimisation may substantially enhance production consistency and quality. Finally, microphysiological systems—particularly advanced multi-organ-chip platforms and 3D-bioprinted tissue constructs—bridge the critical gap between in vitro studies and clinical outcomes by faithfully recapitulating human inflammatory microenvironments, thus generating physiologically relevant preclinical data on PNPs under haemodynamic conditions and multi-cellular crosstalk. Collectively, addressing these challenges will not only advance the clinical translation of PNPs but also unlock their potential as precision therapeutic platforms for targeting inflammation-associated pathologies.

Search strategy and selection criteria.

Relevant literature was systematically retrieved from PubMed, Web of Science, and Scopus. The search strategy encompassed terms such as inflammation modulation, polymeric nanoparticles, nanomedicine, targeted drug delivery, stimuli-responsive systems, and immune regulation. Focus was placed on studies investigating the design, mechanisms, therapeutic efficacy, and immune modulation of PNPs, while excluding research on non-polymeric nanoparticles and articles with insufficient experimental data. Only peer-reviewed articles published in English were considered. Selected articles were mutually agreed upon by all authors.

Contributors

Hailin Zhang: data curation, writing–original draft, writing–review & editing. Haoxiang Chen: conceptualisation, writing–original draft, writing–review & editing. Xinman Hu: writing–original draft, data curation. Wali Muhammad: data curation, writing–original draft. Chenyu Liu: investigation, data curation, conceptualisation. Wenxing Liu: supervision, writing–review & editing. All of the authors read and approved the final manuscript.

Declaration of interests

The authors declare no potential conflicts of interest.