Nanomaterial-Based Strategies Targeting IL-1 Signalling in Inflammatory Bowel Disease: Therapeutic Applications and Mechanistic Insights

Abstract

Inflammatory Bowel Disease (IBD) is a group of gastrointestinal disorders characterized by chronic relapsing inflammation, primarily comprising Ulcerative Colitis and Crohn’s Disease. Interleukin(IL) −1 (IL-1) family plays a central role in the immunoregulation of IBD, where its aberrant activation amplifies inflammatory responses through nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, leading to excessive release of pro-inflammatory cytokines, disruption of the epithelial barrier, and mucosal damage. Although biological agents targeting IL-1, such as Anakinra and the neutralizing antibody Canakinumab, have demonstrated anti-inflammatory effects in animal studies and certain clinical trials, challenges including low bioavailability, short half-life, and insufficient targeting specificity remain unresolved. In recent years, the emergence of nanomaterial technology has provided novel insights for the precise modulation of IL-1 signaling through two principal strategies. By loading IL-1 blockers or regulatory molecules into targeted and environmentally responsive nanoplatforms, it is possible to achieve site-specific drug delivery and sustained release at inflammatory loci, significantly reducing local inflammation and promoting mucosal repair. Specifically, we highlight advanced nanotechnology platforms—including lipid-based nanocarriers, polymeric nanosystems, inorganic nanomaterials, and bio-derived vesicles—that enable stimuli-responsive drug release, active mucosal targeting, and intrinsic immunomodulation to overcome biological barriers in the gut. Notably, certain active nanomaterials can directly eliminate reactive oxygen species (ROS) and block NLRP3 inflammasome activation to suppress IL-1 production. This review summarizes the role of the IL-1 family in the pathogenesis of IBD and advances in nanomaterial-based targeting strategies. Furthermore, by exploring Quality-by-Design (QbD) approaches and personalized nanocarriers, we aim to provide a new theoretical foundation and research direction for the evolution of IBD therapy toward stratified precision medicine.

Graphical Abstract

Introduction

Inflammatory bowel disease (IBD) is a chronic, immune-related, and nonspecific inflammatory disorder of the gastrointestinal tract, encompassing two major forms: ulcerative colitis (UC) and Crohn’s disease (CD). Affecting approximately 3.32 million individuals worldwide, its incidence has risen by nearly 47% over the past 15 years.¹ The pathogenesis of IBD remains incompletely understood; however, immune dysregulation is recognized as a key driver of disease initiation and progression. Crucially, this immune dysregulation arises from a tripartite interaction between gut microbiota, epithelial barrier integrity, and inflammatory signaling. Gut microbiota dysbiosis is now recognized as a major contributor to this process. Through the microbiota-immune axis, specific intestinal microbial colonization directly triggers the production of pro-inflammatory cytokines, including IL-1, and drives downstream inflammatory cascades.² Barrier impairment facilitates mucosal infiltration by microbial components, triggering pathologic immune responses. Specifically, microbial stimuli activate the TLR4-NF-κB pathway by promoting K48-linked IκBα ubiquitination, thereby intensifying intestinal inflammation.³ Clinically, patients typically present with abdominal pain, diarrhea, and mucus- or blood-stained stools. In severe cases, persistent inflammation markedly increases the risk of colorectal cancer, profoundly impairing quality of life.⁴ Although glucocorticoids and immunosuppressive agents have achieved partial therapeutic success, a substantial proportion of patients exhibit poor responsiveness, drug resistance, or serious adverse effects. Therefore, there is an urgent need for novel targeted therapeutics to overcome the current challenges in IBD management.⁵

Among the numerous immune-mediated signaling pathways implicated in IBD, the Interleukin(IL) −1 (IL-1) family has emerged as a central orchestrator of intestinal inflammation. This cytokine family—comprising Interleukin(IL)-1 alpha (IL-1α), Interleukin(IL)-1 beta (IL-1β), Interleukin(IL)-18 (IL-18), Interleukin(IL)-33 (IL-33), Interleukin(IL)-36 (IL-36), Interleukin(IL)-37 (IL-37), and Interleukin(IL)-38 (IL-38)—maintains mucosal immune homeostasis through a delicate balance between proinflammatory and anti-inflammatory members.⁶ IL-1β, the most prominent proinflammatory cytokine of this family, activates downstream NF-κB and MAPK signaling via binding to the IL-1 receptor type I (IL-1R1), thereby inducing the release of multiple inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and IL-6, and disrupting epithelial tight junctions, leading to barrier dysfunction.⁷ Clinical studies have demonstrated that IL-1β expression is markedly elevated in both colonic tissues and peripheral mononuclear cells of IBD patients, correlating positively with disease activity.⁸ Conversely, anti-inflammatory cytokines such as IL-37 and IL-38 suppress NF-κB signaling and proinflammatory gene transcription, thereby attenuating mucosal inflammation and restoring immune balance.⁹ For instance, administration of IL-37 significantly reduces mucosal injury scores and inflammatory cell infiltration in experimental colitis model.¹⁰ Collectively, these findings highlight the IL-1 family as a critical immunoregulatory axis in IBD pathogenesis, suggesting that modulation of IL-1 signaling could enable precise control of intestinal inflammation.

Targeted inhibition of IL-1 signaling has achieved preliminary clinical success. The IL-1 receptor antagonist Anakinra has been shown to alleviate symptoms in patients with refractory Crohn’s disease, whereas the IL-1β-neutralizing antibody Canakinumab effectively reduces inflammation and improves colonic histopathology in preclinical models.^11,12 Nonetheless, these biologics still face several limitations, including systemic immunosuppression, short plasma half-life, limited accumulation at intestinal lesions, and suboptimal delivery efficiency.¹³ Given that IBD primarily involves localized intestinal inflammation, achieving site-specific and sustained drug release within the gut microenvironment remains a major therapeutic challenge.

Recently, nanotechnology has provided an innovative platform for IL-1-targeted therapy. Specifically, nanoscale delivery systems resolve the fundamental bottlenecks of conventional biologic therapies. These platforms transport drugs directly to the inflamed mucosa, shield sensitive therapeutics from gastrointestinal degradation, and drive microenvironment-responsive release. As recent evidence on targeted nanoplatforms demonstrates, optimizing carrier design significantly enhances structural stability, extends local retention, and maximizes overall efficacy by minimizing rapid systemic clearance.¹⁴ Owing to their tunable physicochemical properties and superior biocompatibility, nanocarriers can enable active or passive targeting of inflammatory sites, thereby enhancing drug bioavailability while minimizing systemic toxicity.¹⁵ Beyond traditional particulate nanocarriers, this therapeutic strategy has naturally expanded to include macroscopic systems. While platforms like lipid nanoparticles and exosomes function as free-flowing nanoscale vehicles, hydrogels serve as macroscopic, three-dimensional localized depots—even when they incorporate internal nanoscale porosity. Together, these diverse platforms—including natural polysaccharide- and protein-based carriers, hydrogels, lipid nanoparticles, exosome-based systems, as well as probiotic and prebiotic delivery vehicles, have been engineered to deliver therapeutic agents to the inflamed mucosa, improve drug stability, and achieve controlled release—addressing the limitations of conventional therapies.^16,17 To bridge the critical therapeutic gap left by the insufficient mucosal targeting and systemic side effects of current immunotherapies, the overarching aim of this review is to systematically evaluate how rapidly evolving nanomaterial platforms can precisely target IL-1 signaling for clinical IBD management. The dual strategies of nanomaterial-mediated IL‑1 pathway modulation for IBD treatment are schematically illustrated in Figure 1.

Figure 1.

Schematic illustration of nanomaterial-based dual strategies for IL-1 pathway modulation in inflammatory bowel disease. (A) Nanocarrier-based IL-1 inhibitor delivery strategy: Nanocarriers such as liposomes, polymeric microspheres, hydrogels, and exosomes encapsulate IL-1 inhibitors to achieve targeted delivery to inflamed sites with controlled release. (B) Nanomaterial-based direct inhibition strategy of IL-1 production: Bioactive nanomaterials themselves modulate the immune microenvironment and suppress the transcription of pro-inflammatory cytokines such as IL-1, thereby promoting intestinal barrier repair.

Mechanisms and Roles of IL-1 Family Cytokines in Regulating IBD Progression

Immunodysregulation Mechanisms in IBD

IBD is a chronic, relapsing, immune-mediated disorder characterized by dysregulated interactions between the innate and adaptive immune systems. The core pathogenic process involves an imbalance between proinflammatory and regulatory immune responses. Increasing evidence indicates that members of the IL-1 cytokine family play pivotal roles in orchestrating this immune disequilibrium by bridging the initiation of mucosal inflammation with the amplification of adaptive immune responses.

In the early stages of IBD, intestinal epithelial cells and macrophages respond to microbial stimuli by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, leading to the secretion of IL-1β and IL-18. IL-1β promotes dendritic cell (DC) maturation and antigen presentation, while enhancing their production of IL-6 and IL-23, thereby driving the differentiation and expansion of T helper 17 (Th17) cells.¹⁸ Activated Th17 cells secrete proinflammatory cytokines, including IL-17A, IL-17F, IL-21, and IL-22, which stimulate epithelial cells and macrophages to produce TNF-α and IL-6, forming a self-perpetuating inflammatory amplification loop. Moreover, IL-21 upregulates the IL-23 receptor on Th17 cells, sustaining their activation and reinforcing chronic inflammation.¹⁹ Concurrently, IL-1β directly impairs the suppressive function of regulatory T cells (Tregs), disrupting the Th17/Treg balance and leading to the breakdown of mucosal immune tolerance. Conversely, Tregs maintain intestinal homeostasis primarily through the secretion of anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-β).²⁰ In IBD, persistent activation of IL-1 signaling induces Smad7 overexpression, thereby inhibiting the TGF-β/Smad pathway and weakening Treg-mediated immunosuppression. In addition, co-stimulation by IL-6 and IL-1β suppresses Forkhead box P3 (Foxp3) expression, converting a subset of Tregs into Th17-like cells, further amplifying the proinflammatory cascade.²¹ This positive feedback loop perpetuates local intestinal inflammation and hinders resolution.

At the innate immune level, innate lymphoid cells (ILCs) are also modulated by IL-1 family cytokines. IL-18 promotes ILC1 to secrete interferon gamma (IFN-γ) and TNF-α, thereby strengthening Th1-type immune responses. Under the stimulation of IL-12 and IL-18, ILC1s upregulate the transcription factor T-bet, contributing to subtype plasticity and functional reprogramming.¹⁶ ILC2s, by contrast, produce IL-4, IL-5, and IL-13 to enhance mucin secretion from epithelial cells and recruit eosinophils, thereby participating in barrier defense.¹⁷ ILC3s secrete IL-17 and IL-22, which are crucial for maintaining epithelial tight junction integrity and inducing antimicrobial peptide expression. Notably, impaired function or reduced numbers of ILC3s in IBD patients have been linked to epithelial barrier disruption, bacterial translocation, and exacerbated inflammation.²² Additionally, regulatory innate lymphoid cells (ILCregs) play a protective role by secreting IL-10 to suppress excessive activation of ILC1 and ILC3, thus reducing IFN-γ and IL-17 production. ILCregs also promote CD4⁺ T-cell differentiation toward the Treg phenotype, thereby restoring immune tolerance. Moreover, ILCregs release growth factors such as epidermal growth factor (EGF), which facilitate epithelial regeneration and barrier repair, ultimately contributing to the restoration of intestinal homeostasis.²³ The roles of innate lymphoid cells and related immune mechanisms in IBD are summarized in Figure 2.

Figure 2.

Immune mechanisms in IBD. Factors such as intestinal bacterial infection can promote the expression of inflammatory factors through the activation of macrophages. TNFα, IFNα, IL-12 and other cytokines can activate T cells and promote their differentiation into Treg, CD8⁺, CD4⁺, causing the disruption of Th17/Treg balance. Innate immune cells, such as ILC, also play an important role in promoting the progress of IBD.

Mechanisms of Action of the IL-1 Cytokine Family in IBD

IL-1α and IL-1β

IL-1α and IL-1β were the first identified members of the IL-1 family and both initiate downstream signaling by binding to IL-1 receptor I (IL-1R1), which recruits the adaptor complex myeloid differentiation primary response 88 (MyD88)–Interleukin(IL)-1 receptor-associated kinase (IRAK)–TNF receptor-associated factor 6 (TRAF6) to activate NF-κB and MAPK pathways.²⁴ IL-1β potentiates monocyte-macrophage and dendritic cell activation, promoting the release of TNF-α, IL-6, and IL-23 to drive Th17 differentiation and sustain intestinal inflammation.^18,25 It also induces degradation of epithelial tight-junction proteins, leading to barrier dysfunction and facilitating translocation of luminal bacterial products, thereby perpetuating chronic immune activation.²⁶ IL-1α, in contrast, is predominantly stored in necrotic epithelial cells and acts as a damage-associated molecular pattern (DAMP) that rapidly triggers local immune activation upon release.²⁷

Il-18

Similar to IL-1β, IL-18 requires inflammasome-mediated cleavage for activation.²⁸ Upon binding to its receptor complex IL-18Rα/β, IL-18 activates MyD88-NF-κB signaling to promote ILC1 and Th1 secretion of IFN-γ and TNF-α, thereby strengthening cell-mediated inflammatory responses.¹³ Under physiological conditions, IL-18 enhances epithelial secretion of mucus and antimicrobial peptides to maintain barrier defense; however, its overactivation in IBD increases epithelial apoptosis and impairs tissue regeneration.²⁹ Thus, IL-18 exerts a dose-dependent dual effect—protective under homeostatic conditions but pathogenic when chronically activated.

Il-33

IL-33 acts as an epithelial-derived “alarmin” released upon cell necrosis or mechanical injury. It signals through the suppression of tumorigenicity 2 (ST2) receptor to activate MyD88-NF-κB and MAPK pathways.³⁰ IL-33 primarily promotes Th2 responses and ILC2 activation, stimulating IL-5 and IL-13 production which drives eosinophil infiltration and epithelial restitution.^14,31 Experimental models suggest that IL-33/ST2 signaling exerts mucosal-protective effects during the acute phase of inflammation but promotes fibrosis and tissue remodeling under chronic exposure.³² Hence, IL-33 has a context-dependent dual role in IBD, balancing repair and pathological remodeling according to the inflammatory milieu.

Il-36

IL-36α, IL-36β, and IL-36γ bind to IL-36R and activate NF-κB and MAPK signaling to induce chemokines such as IL-8 and Chemokine (C-X-C motif) ligand 1 (CXCL1), thereby recruiting neutrophils to inflamed tissues.³³ IL-36γ expression is markedly elevated in the colonic tissues of IBD patients and correlates positively with disease activity.³⁴ Excessive IL-36 activation amplifies innate immune inflammation and promotes Th17 differentiation, sustaining chronic inflammatory circuits.³⁵ Conversely, IL-36Ra serves as an endogenous antagonist that competitively binds IL-36R to suppress downstream signaling and mitigate tissue injury.³⁶

Il-37

IL-37 functions as a natural immune suppressor by forming a receptor complex with IL-18Rα and the co-receptor IL-1R8 (SIGIRR), thereby inhibiting NF-κB and MAPK activation and downregulating TNF-α, IL-6, and IL-1β production.³⁷ In experimental colitis models, IL-37 overexpression markedly reduces histological inflammation, limits myeloid-cell infiltration, and preserves epithelial integrity.³⁸ Additionally, IL-37 suppresses NLRP3 inflammasome activation and oxidative stress, disrupting the inflammatory amplification loop.³⁹

Il-38

Structurally related to IL-1Ra, IL-38 binds to IL-36R and attenuates its proinflammatory signaling.⁴⁰ It is highly expressed in healthy intestinal mucosa but markedly reduced in IBD patients.⁴¹ IL-38 suppresses IL-6 and IL-1β release from dendritic cells and macrophages, promotes Treg differentiation, and restores the Th17/Treg balance.⁴² Moreover, IL-38 inhibits complement overactivation, thereby reducing tissue injury.¹⁰

The Role of IL-1 Family in Downstream Signalling Pathways via Coreceptors

The IL-1 receptor family consists of several members, including IL-1R1, IL-1R2, Interleukin(IL) −1 receptor accessory protein (IL-1RAcP), ST2, IL-18Rα, IL-36R (IL-1Rrp2), IL-18Rβ, TIR8, IL-1R9, IL-1R10.⁴³ These receptors, while binding specific cytokines, share the ability to activate the Toll/interleukin-1 receptor (TIR) signaling pathway upon ligand binding.⁴⁴ Upon activation of the TIR domain, MyD88 recruits IRAK via death domain interactions. IRAK undergoes phosphorylation, enabling its association with TRAF6. This activates two distinct downstream signaling cascades, leading to the activation of c-Jun N-terminal kinase (JNK) and NF-κB pathways.⁴⁵ Consequently, there is an upregulation of pro-inflammatory mediators, including TNF-α, IL-1β, IL-17, monocyte chemoattractant protein (MCP), IL-6, IL-8, IFN-γ, IL-23, CCL-2, IL-22, IL-10, CCL-7, IRAK, and TGF-β, contributing to the inflammatory response.⁴⁶ The signaling pathway and inflammatory responses mediated by the IL‑1 family are illustrated in Figure 3.

Figure 3.

The IL-1 family of cytokines binds to receptors, activating TIR, which in turn activates Activating transcription factor (ATF), NF-κB, and Activator protein 1 (AP-1) pathways through MyD88 and IRAK. This process leads to the production of a large number of inflammatory cytokines, including NF-α, IL-1β, IL-17, MCP, IL-6, IL-8, IFN-γ, IL- 23, CCL-2, IL-22, IL-10, CCL-7, IRAK, TGF-βand so on, thereby promoting inflammation.

Research Progress and Limitations of Existing IL-1-Targeted Therapies for IBD

Targeting IL-1 represents a rational therapeutic strategy in IBD, as IL-1 family cytokines serve as upstream amplifiers of both innate immunity and adaptive mucosal inflammation. A series of biological agents and biologics-like compounds, including receptor antagonists, neutralizing monoclonal antibodies, soluble trapping agents, and cytokine-binding proteins, have been developed to block IL-1 family signaling.

Anakinra, a recombinant human IL-1Ra, competitively inhibits the binding of IL-1α/IL-1β to IL-1R1, thereby suppressing downstream MyD88-dependent NF-κB and MAPK activation. Mendelian randomization studies by Mi et al demonstrated an inverse correlation between IL-1Ra levels and risk of IBD subtypes, suggesting the therapeutic potential of IL-1Ra agents like anakinra for IBD.⁴⁷ Current evidence from small case series and exploratory studies indicates potential benefits in specific steroid-refractory inflammatory conditions and particular intestinal inflammation scenarios, though high-quality randomized controlled trials (RCTs) in IBD are lacking. For instance, Dogan et al reported that anakinra may provide significant clinical benefits in patients with IL-10R beta deficiency, serving as a bridge to definitive treatment with hematopoietic stem cell transplantation (HSCT).⁴⁸ Additionally, Truyens et al described a UC patient who developed severe complications following azathioprine treatment, with cytokine profiling revealing elevated IL-1Ra, potentially indicating an IL-1-mediated autoinflammatory syndrome with corticosteroid-dependent UC flares; anakinra administration rapidly resolved systemic inflammation and UC symptoms.⁴⁹ However, a randomized trial in Acute Severe Ulcerative Colitis (ASUC) demonstrated that adding anakinra to intravenous corticosteroids provided no significant improvement in symptom control or clinical outcomes, with most patients still requiring rescue therapy.⁵⁰ Furthermore, anakinra’s short terminal half-life (approximately 4–6 hours) necessitates daily subcutaneous administration, creating challenges for sustained target coverage and maintenance therapy.⁵¹

Canakinumab, a human monoclonal antibody that neutralizes IL-1β, prevents its receptor activation and subsequent inflammatory cascades. While canakinumab has demonstrated clear clinical benefits in various systemic autoinflammatory syndromes including Cryopyrin-Associated Periodic Syndrome (CAPS), Familial Mediterranean Fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), and Schnitzler syndrome, evidence in IBD remains limited to small case series, primarily involving very early-onset or autoinflammatory-phenotype patients.^52–54 A representative clinical case of Cryopyrin-Associated Periodic Syndrome (CAPS) provides clear evidence of IL-1β–driven inflammation and the therapeutic efficacy of its targeted inhibition. A Japanese female patient exhibited early-onset manifestations, including urticaria-like rashes on the trunk and limbs from infancy. At approximately four years of age, she developed bilateral knee arthritis accompanied by intermittent fever. Genetic analysis identified a mosaic NLRP3 mutation (E567K), confirming the diagnosis of CAPS. Administration of canakinumab, a selective IL-1β inhibitor, led to immediate resolution of fever and rash. This rapid clinical improvement illustrates the pivotal role of IL-1β hyperactivation in CAPS pathogenesis and underscores the capacity of canakinumab to achieve prompt and sustained symptom control in early-onset cases.⁵⁵ Although some patients exhibited significant responses, large-scale RCT data in IBD populations are still absent. Furthermore, several other therapeutic agents targeting IL-1 family cytokines are currently under clinical investigation primarily for other disease models, with relevant details summarized in Table 1.

Table 1.

Monoclonal Antibody Blocking Cytokines in Clinical Trial

Target	Medicine	Mechanism	Disease	Clinical Trial	Effect	NCT	Reference
IL-1Ra	Anakinra	Cytokine receptor antagonists	Autoimmune inner ear disease (AIED)	I/II	IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse.	NCT01267994	[56]
IL-1Ra	Kineret	Cytokine antagonists	Gastrointestinal mucosal barrier injury	II	Kineret can prevent acute mucosal barrier injury and have a good safety profile.	NCT03233776	[57]
IL-1α	LACTIN-V	Soluble receptors	Bacterial vaginosis	II	Lactin-V after vaginal metronidazole treatment for bacterial vaginosis resulted in a significantly lower incidence of bacterial vaginosis recurrence at 12 weeks compared with placebo, and the benefit appears to persist into week 24.	NCT02766023	[58]
IL-1α	Abatacept	Selective co-stimulation	Refractory chronic graft-versus-host disease after allogeneic transplantation	II	In the study, Brazil was well tolerated, with 58% of patients improving chronic graft-versus-host disease while reducing steroid use.	NCT01954979	[59]
IL-1β	Canakinumab	Cytokine antagonists	Schnitzler’s syndrome	II	Monthly 150 mg canakinumab injection was an effective and well-tolerated treatment for Schnitzler’s syndrome.	NCT01276522	[60]
IL-1β	Canakinumab	Cytokine antagonists	Colchicine-resistant familial Mediterranean fever; mevalonate kinase deficiency; TNF receptor-associated periodic syndrome	III	Canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TNF receptor-associated periodic syndrome.	NCT02059291	[61]
IL-1β	Canakinumab	Cytokine antagonists	Rheumatoid arthritis (RA)	II	The addition of canakinumab 150 mg through subcutaneous injection q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate.	NCT00784628	[62]
IL-1β	Iberdomide	Cytokine antagonists	Systemic lupus erythematosus	II	Administration of a single dose of 0.3–6 mg of iberdomide reduces intracellular Aiolos protein expression in B cells and T cells, reduces the number of T cells and B cells, iberdomide increases T cell-derived IL-2 production and decreases LPS-induced IL-1β production in ex vivo whole blood.	NCT02185040	[63]
IL-18	Tadekinig alfa	Cytokine-binding proteins	Adult-onset Still’s disease	II	Tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in Adult-onset Still’s disease.	NCT02398435	[64]
IL-33	CNTO 7160	Cytokine receptor antagonists	Asthma or atopic dermatitis	I	Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or atopic dermatitis).	NCT02345928	[65]
IL-33	Etokimab	Cytokine antagonist	Peanut allergy	II	Etokimab is safe and well tolerated, and a single dose of etokimab has the potential to desensitize peanut-allergic participants and may reduce atopic-related adverse events.	NCT02920021	[66]
IL-33	Itepekimab	Cytokine antagonists	Asthma	II	As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count.	NCT03387852	[67]
IL-36Ra	Spesolimab	Cytokine antagonists	Generalized pustular psoriasis (GPP)	II	High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks.	NCT04399837	[68]
IL-36Ra	Imsidolimab	Cytokine receptor antagonists	GPP	II	Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29 and through day 113.	NCT03619902	[69]
IL-36Ra	Spesolimab	Cytokine antagonist	GPP	I	A single dose of 10 mg/kg IV spesolimab resulted in rapid (within 7 days) and sustained improvement in clinical signs and symptoms of GPP (until week 20)	NCT02978690	[70]

Targeting the IL-1 pathway demonstrates clear biological rationale in IBD treatment, yet clinical translation faces multiple challenges. Current systemically administered protein-based biologics struggle to achieve sufficient effective concentrations at inflamed intestinal mucosal sites, while systemic IL-1 blockade may increase risks of immunosuppressive infections and cytokine redundancy. Several additional factors contribute to the suboptimal clinical efficacy observed with IL-1-targeted therapies. The development of anti-drug antibodies (ADAs) due to immune dysregulation or incomplete humanization of monoclonal antibodies can lead to treatment failure or hypersensitivity reactions by neutralizing therapeutic effects or altering pharmacokinetics.^71,72

Furthermore, the inherent complexity of cytokine networks means that blocking a single cytokine may trigger compensatory increases in others, disrupt interrelated signaling pathways, or even exacerbate inflammation under specific conditions. For instance, IL-1Ra antagonism has been shown to worsen systemic juvenile idiopathic arthritis (sJIA) through excessive phosphorylation, alter immune cell populations thereby affecting treatment response, and increase susceptibility to infections in patients with autoinflammatory diseases.^73–75 These network effects also extend to compromised anti-tumor immunity via Interleukin(IL)-18 binding protein (IL-18BP)-mediated suppression of recombinant IL-18 (rIL-18) activity and potential induction of eosinophilic inflammation due to oversuppression of IL-36γ and IL-23 in respiratory diseases.^76,77 Collectively, these findings highlight the challenges in achieving precise immunological control without unintended consequences. Additionally, immunogenicity, short half-lives, and delivery limitations of IL-1 inhibitors further compromise treatment durability and safety. Therefore, there is an urgent need to develop targeted delivery strategies that enhance drug exposure at lesion sites while minimizing systemic side effects, ultimately providing superior treatment options for patients.

Nanomaterial-Based Therapeutic Strategies Targeting the IL-1 Family in IBD

Researchers have designed nanomaterial-based strategies targeting the IL-1 family to enable precision therapy for IBD. These strategies operate through two principal mechanisms: targeted delivery of IL-1 inhibitors and suppression of IL-1 production at inflamed sites. At the carrier level, polysaccharide-, protein-, and lipid-based nanoplatforms—such as liposomes and exosomes—can overcome gastrointestinal barriers, concentrate IL-1 inhibitors at inflammatory loci, and provide sustained local release. These carrier systems prolong the half-life of therapeutic agents while minimizing systemic immunosuppression. At the material-activity level, inorganic nanozymes such as Mo₃Se₄ nanoflakes, bioactive glass, and probiotic-loaded nanoparticles reduce inflammatory signaling by eliminating reactive oxygen species (ROS), blocking NLRP3 inflammasome activation, and modulating the NF-κB and MAPK pathways. Some formulations also facilitate epithelial repair and contribute to restoring microbial homeostasis. Collectively, these approaches address the major limitations of conventional IL-1–targeted drugs—namely poor intestinal targeting and low bioavailability—while integrating precise IL-1 signaling regulation with microenvironmental modulation to facilitate clinical translation of precision IBD therapies. A summary of representative IL-1–targeted nanodelivery systems and their anti-inflammatory efficacy is provided in Table 2.

Table 2.

Summary of IL-1–Targeted Nanodelivery Systems and Their Anti-Inflammatory Efficacy

Material	Advantages	Efficacy	Mechanism
114-LNP/siIL-1β	Exhibits acid-responsive siRNA release, high buffering capacity enhancing macrophage uptake, and good biocompatibility.	At 25 nM, silences 78% of IL-1β mRNA in RAW 264.7 cells with inhibitory effects lasting over 5 h.	Protonation under acidic conditions promotes siRNA release and endosomal escape, enabling targeted IL-1β mRNA degradation.78
ANK-SNs	Provides high intracellular delivery efficiency, long-lasting therapeutic effect, and serum stability.	At 10 μg/mL, suppresses IL-17 expression by up to 80% for 5 days	Efficiently delivers recombinant IL-1 receptor antagonist (anakinra) to block IL-1 from binding its receptor.79
DNA Nanoraft/IL-33	Enables precise loading with sustained release, prolonged systemic circulation, and no toxicity or immune activation	Extends IL-33 half-life to more than 24 times that of free IL-33 with 87.8% colocalization at 2 h.	DNA nanostructures control cytokine loading and delivery to improve pharmacokinetics.80
FNV	Provides stable, strong fluorescence for tracking, enhances targeting efficiency 2–3-fold, and maintains biocompatibility.	Displays a half-life of 6–8 h with therapeutic effect lasting 24 h.	The PDI core offers fluorescence, while NALI modification enhances IL-33 binding affinity for targeted delivery.81
ExoCPC-IL-1RA	Demonstrates cartilage-targeting capability, non-immunogenicity, and prolonged half-life.	A single dose sustains efficacy for 8 days and inhibits NF-κB activation by up to 85%.	Cationic peptide-modified milk-derived exosomes encapsulate IL-1RA via sonication to achieve targeted, sustained release.82
GelMA-CS-IL-1Ra	Combines porous architecture and negative charge for dual loading, with sustained release and high compatibility.	Achieves 68.2% cumulative release of IL-1Ra within 20 days, reducing IL-1β by 80% and COX-2 mRNA by 65%.	Electrostatic interactions slow IL-1Ra release and suppress proinflammatory mediators.83
PLGA	Produces strong anti-inflammatory effects with long release duration (56 days) and minimal cytotoxicity.	Sustains IL-1Ra release for 56 days, reducing IL-1β by 82.1%, IL-6 by 70.1%, and TNF-α by 57.4%.	An optimized S/O/W technique prevents protein denaturation, allowing long-term controlled release through the PLGA matrix.84
Mineral-coated IL-1Ra MPs	Supports localized tissue delivery and reduces chronic inflammation and foreign-body response.	The therapeutic efficacy lasts for 14 days, with decreases of 72.9% for IL-1α and 52.4% for IL-1β.	Mineral coating provides a depot for localized, sustained IL-1Ra release at inflammatory sites.85
IL-1Ra CS/β-GP/Gel	Features thermal sensitivity for injectability, long release period, and suitability for long-term use.	Exhibits a half-life of 21 days with 83.23% cumulative release, reducing IL-1β by 33.3%, IL-6 by 56%, and TNF-α by 51.6%.	Forms a gel at 37 °C for an initial burst followed by sustained release.86
GK-PF127	Remains liquid at room temperature and gels in vivo, protecting IL-1Ra and extending its half-life.	Prolongs half-life to 12.53 h with efficacy lasting 24 h, reducing IL-6 by 60%.	PF127 forms an in situ gel depot encapsulating IL-1Ra for controlled release.87
IL-1Ra/G-MSCs/HA-sECM	Combines mesenchymal stem cells with IL-1Ra for synergistic anti-inflammatory effects.	After an initial rapid release, maintains steady drug levels; G-MSC viability 92.3%; reduces MMP-9 by 70.1% and TNF-α by 76.4%.	Co-delivery of IL-1Ra and gingival MSCs within a hyaluronic acid scaffold modulates inflammation and supports tissue repair.88
IL-1Ra/rhBMP-2/CHA	Integrates growth factors to avoid bone resorption and provide immunomodulatory synergy.	After an initial burst, continues release for 7 days while maintaining an IL-1Ra/IL-1β ratio >10 to inhibit IL-1β signaling.	Co-delivery platform sustains the IL-1Ra/IL-1β balance to suppress inflammation and promote bone regeneration.89
PPE-NPs	Protects active components from degradation and enables targeted, controlled release.	At 150 mg/kg, reduces IL-1β by 56.2%, restoring it close to normal levels.	Inhibits inflammatory signaling and lowers TNF-α, IL-1β, CXCL-9, CXCL-10, and nitric oxide (NO) levels.90
C@MNS@DMBe-S	Enzyme- and pH-responsive targeted release with synergistic drug effects and mucosal healing promotion.	Suppresses NLRP3 activation, decreases IL-1β and IL-18 release, and upregulates TGF-β to 2.2-fold above baseline.	Inhibits the NLRP3/NF-κB pathway and enhances TGF-β signaling, achieving anti-inflammatory and epithelial repair effects.91
CZNH	Improves water solubility and thermal stability; demonstrates efficacy superior to free curcumin.	Reduces IL-1β (23.2%) and TNF-α (33.7%), doubling the effect of free curcumin.	Scavenges ROS, blocks upstream NLRP3 inflammasome activation, and inhibits caspase-1 and pro-IL-1β cleavage.92
AG/CORM-2@NP	Offers oral delivery with good biocompatibility, sustained release, and biodegradability.	Reduces IL-1β by ~70% and IL-6 by ~69%.	Releases AG/CORM-2 to lower excessive NO production and downregulate TNF-α, IL-1β, and IL-6 expression.93
BANPs	Enhances probiotic viability and targeted delivery; prolongs systemic circulation.	In colon homogenate, reduces IL-1β (65%), TNF-α (33.3%), and IL-6 (80%) compared with DSS group.	Inhibits NF-κB and MAPK phosphorylation, blocking IL-1β transcription and AP-1 activation.94
ZPNs	Pectin coating enhances stability and controlled release, achieving strong therapeutic efficacy.	Downregulates COX-2 (39.7%), CSF-1 (80%), IL-6 (80.5%), and TNF-α (54.65%) mRNA levels.	Prevents NF-κB p65 nuclear translocation to reduce cytokine secretion.95
Tau-CS-PT-NPs	Enables site-specific release in response to intestinal enzyme degradation and protects drug from gastric acid.	Lowers colonic IL-1β levels by 62% compared with model group	Taurine reacts with HOCl at inflammatory sites to form Tau-Cl, inhibiting NF-κB activation and IL-1β transcription.96
CR@GA-GMS hydrogel	Exhibits inflammation-targeted adhesion and localized high-concentration release via multiple synergistic pathways.	Significantly reduces TNF-α and IL-1β expression and decreases nitrite and MPO activity.	CR downregulates HIF-1α and indirectly inhibits NF-κB; GA scavenges mitochondrial ROS, disrupting the ROS-TXNIP-NLRP3 axis.97
Lipid-based “bomb effect” nanosystem	Provides high therapeutic precision and potent anti-inflammatory activity.	Reduces TNF-α by 44.4% and IL-1β by 46.9%.	Downregulates CD98 gene expression via siCD98, reducing pro-inflammatory cytokine release.98
58SBG	Features controllable hierarchical structure with synergistic Si/Ca regulation.	Decreases IL-6 (46.2%) and TNF-α (51.8%).	Suppresses TLR4/MyD88/NF-κB signaling activation to reduce pro-inflammatory cytokines.99
PMNFs	Possesses strong antioxidant capacity and enhanced stability.	Lowers IFN-β (48.2%), IL-1β (68.6%), IL-6 (51.1%), and TNF-α (51.1%).	Inhibits TLR4-mediated NF-κB activation and scavenges ROS.100
ASBE–Ag-NPs	Exhibits high bioavailability and targeting ability derived from natural sources.	Restores pro-inflammatory cytokine levels close to normal; COX-2 inhibition rate ~65%.	Suppresses COX-2 expression and PGE2 production, blocking PGE2-mediated IL-1β and TNF-α synthesis.101
SFELNVs@CX5461	Demonstrates oral stability and high targeting efficiency, overcoming limitations of intravenous delivery.	Compared with UC group, reduces IL-6 by 60% and IL-1β by 65%.	Inhibits NF-κB signaling, downregulates TNF-α and IL-6, suppresses STAT1 phosphorylation, and blocks M1 macrophage polarization.102
Akk EVs	Restores gut microbiota balance and supports mucosal repair and maintenance.	Decreases IL-6 from 65 pg/mL to 50 pg/mL.	Promotes growth of beneficial bacteria, upregulates ZO-1 and MUC2, and strengthens epithelial barrier to reduce cytokine secretion.103
PELNs	Ensures oral safety, stability, and site-specific targeting of inflamed tissue.	Significantly reduces IL-6, IL-12, IL-1β, and TNF-α while increasing IL-10.	Activates AhR, downregulates Zbtb7b, and reprograms conventional CD4⁺ T cells into CD4⁺CD8⁺ T cells.104
mEVs	Enables scalable production, high stability, enzyme resistance, and low cost.	1010 mEVs reduce IL-1β expression by ~65% and restore IL-17 close to baseline.	Prevents IκBα degradation and NF-κB nuclear translocation; inhibits p38/JNK hyperactivation and modulates ERK to reduce AP-1 activity.105
Mag@CS-Zein NPs	Integrates nanoparticle targeting with microsphere protection for cascade drug delivery.	At 5 µm dose, decreases IL-1β (25.7%), TNF-α (22.5%), and IL-6 (62.5%).	Regulates MAPK, NF-κB, and PPAR-γ pathways and upregulates tight-junction proteins to enhance barrier repair.106
ER-hydrogel	Provides excellent sustained-release behavior and high drug-loading efficiency (97%).	Reduces IL-1β and TNF-α by 60% and 58%, respectively.	Releases budesonide at inflammatory sites, blocking NF-κB signaling and inhibiting IL-1β transcription.107
BBLNPs	Greatly enhances probiotic survival under gastrointestinal conditions via multiple anti-inflammatory mechanisms.	Suppresses TNF-α expression by up to 63.7%.	Downregulates NLRP3 mRNA, inhibits pro-IL-1β activation, promotes M2 macrophage polarization, and increases Treg while suppressing Th17.108
LrEVs	Coordinates immune modulation through the “probiotic-vesicle-immune cell” axis to restore intestinal immune balance.	Compared with control, reduces TNF-α (60%), IL-1β (72.2%), IL-6 (50%), and increases IL-10 expression 5-fold.	Inhibits NF-κB signaling to reduce pro-inflammatory cytokine production and enhance anti-inflammatory activity.109

Enhanced Mechanisms of IL-1 Inhibitor Delivery via Nanocarriers

Nanocarriers enhance the therapeutic efficacy of IL-1 inhibitors by improving drug solubility, protecting bioactive molecules from gastrointestinal degradation, and strengthening targeted delivery to inflamed intestinal regions. The main nanocarrier platforms include liposomes, polysaccharide nanoparticles, protein-based nanoparticles, and exosomes. Liposomes, which share structural similarity with cell membranes, help facilitate fusion and absorption at the intestinal epithelium.Polysaccharide carriers such as chitosan and sodium alginate adhere to inflamed tissue and prolong local drug retention through their inherent mucoadhesive properties. Exosomes derived from cellular membranes exhibit natural immunocompatibility and biological recognition, allowing selective uptake by phagocytes at inflammatory sites and ensuring efficient drug transport. Surface modification with targeting ligands—such as anti-Intercellular Adhesion Molecule 1 (ICAM-1) antibodies or mucosal addressin cell adhesion molecule-1 (MAdCAM-1)-binding peptides—further improves mucosal-targeting precision at inflamed intestinal sites.

Researchers formulate lipid-based nanocarriers with various lipid components. Because these materials share structural similarity with biological membranes, they show high biocompatibility and can effectively deliver nucleic acids, proteins, and other bioactive substances.¹¹⁰ In specific applications, researchers prepare a quaternary ionizable lipid nanoparticle system (114-Ionizable Lipid Nanoparticle/small interfering Interleukin-1 beta) by nanoprecipitation using ionizable lipids, cholesterol, 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG), and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Under acidic conditions, the Lipid nanoparticles (LNPs) undergo protonation, which promotes small interfering RNA (siRNA) release and enables endosomal escape. The linear polyamine structure of 114-LNP increases buffering capacity and enhances macrophage uptake. Beyond enhancing delivery efficiency, these LNPs effectively maintain the biological activity of fragile siRNA. Experimental results demonstrate that LNPs markedly suppress IL-1β expression. In Raw 264.7 cells, 114-LNP/siIL-1β silences 78% of IL-1β mRNA at a siRNA dose of 25 nM. Silencing efficiency increases with higher siRNA concentrations, and the inhibitory effect persists for over 5 hours. Evaluated in an in vivo LPS/D-GalN-induced acute liver injury mouse model, These LNPs maintain high biocompatibility, cause no cellular or tissue toxicity, and significantly prolong the systemic half-life to approximately 6–12 hours, overcoming the rapid clearance of free drugs.⁷⁸ Researchers have also developed sphingomyelin nanosystems loaded with recombinant IL-1 receptor antagonist (anakinra-loaded SNs) that demonstrate strong biological performance. This system combines unloaded sphingomyelin nanosystems (SNs)—composed of vitamin E, sphingomyelin, and surfactant lipids—with the recombinant protein Anakinra (ANK). Compared with unloaded SNs, ANK-SNs achieve higher cellular internalization efficiency. At a therapeutically relevant local concentration of 10 ug/mL, corresponding to the high-nanomolar range required for antagonizing receptor binding,ANK-SNs suppress IL-17 expression by up to 80%, exceeding the 60% inhibition achieved by free ANK, and sustain the effect for up to 5 days. ANK-SNs exhibit minimal cytotoxicity and retain serum stability for at least 48 hours at 37 °C.⁷⁹

Exosomes, as a prominent class of bio-derived carriers, are lipid bilayer vesicles that serve as efficient nanocarriers for drug delivery because of their natural targeting ability and low immunogenicity.¹¹¹ In one study, researchers developed a cytokine delivery platform based on a DNA nanoraft. The core component, the DNA nanoraft, consists of oligonucleotide chains and a rectangular DNA origami nanostructure. Following IL-33 modification and fluorescent labeling, the platform enabled precise quantitative loading and sustained release, effectively preserving the biological activity of IL-33 against rapid physiological degradation. Evaluated in an in vivo mouse model of renal ischemia-reperfusion injury, experimental results showed that considering the short physiological half-life of free IL-33 (<2 h) and the necessity of maintaining high local concentrations to activate renal-resident ILC2s and Tregs, IL-33 delivered by the DNA nanoraft remained in vivo for more than 48 hours, with a half-life 24 times longer than that of free IL-33, and reached a colocalization efficiency of 87.8% at 2 hours. Specifically, the nanoraft group received 0.15 ug IL-33 per dose for only two administrations, whereas the free IL-33 group required five consecutive daily injections at the same dose to achieve comparable therapeutic effects. The system induced no detectable toxicity or immune activation, demonstrating strong potential as a therapeutic candidate.⁸⁰ Another nanocarrier, the fluorescent nanovector (FNV), is based on perylene diimide (PDI). It uses a PDI (Perylenediimide) core that provides stable and strong fluorescence, while Poly(N-acryloyl-L-isoleucine) (NALI) modification enhances the binding affinity with IL-33. The FNV exhibits fluorescence intensity markedly higher than that of free IL-33 and demonstrates a two- to three-fold increase in targeting efficiency. Beyond merely improving targeting, the FNV shows a half-life of approximately 6–8 hours and maintains therapeutic efficacy for up to 24 hours.

Its hemolysis rate remains below 5%, indicating excellent biocompatibility and safety for therapeutic applications.⁸¹ Researchers have also developed a novel cartilage-targeting delivery system, Exosome–Cationic Peptide Carrier–Interleukin-1 Receptor Antagonist (ExoCPC-IL-1RA). In this system, a cationic peptide carrier (CPC) rich in arginine is used to modify the surfaces of milk-derived exosomes. Interleukin-1 receptor antagonist (IL-1RA) is encapsulated into these cationic exosomes via ultrasonication to enable sustained release. Importantly, this exosome platform effectively preserves the biological activity of IL-1RA. At a concentration of 5000 ng/mL, ExoCPC-IL-1RA suppresses IL-1α-induced catabolic activity for up to 16 days, in an early-stage osteoarthritis cartilage explant model, while a single administration maintains therapeutic efficacy for eight days. The milk-derived exosome matrix is non-immunogenic and well tolerated, extending the half-life of IL-1RA to 5–7 days compared with the free form. Under ExoCPC-IL-1RA treatment, NF-κB activation is inhibited by up to 85%, significantly reducing pro-inflammatory cytokine levels.⁸² The assembly and anti-inflammatory efficacy of the DNA nanoraft are detailed in Figure 4.

Figure 4.

Anti-inflammatory mechanism of the DNA nanoraft. (A) Schematic illustration of the nanoraft assembly: IL-33 was conjugated to single-stranded DNA via the SPDP chemical linker and subsequently co-assembled with the rectangular DNA origami nanostructure (Rec-DON) to form the nanoraft. (B) Fluorescence images of kidney sections 12 hours after intravenous injection of Alexa488-labeled IL-33 or Alexa488-labeled nanoraft (n=3). (C) Representative micrographs of H&E and PAS staining of kidney tissues from different treatment groups (n=5). (D) Fluorescence signal intensity of Alexa488-IL-33 and Alexa488-nanoraft in the heart, lung, spleen, pancreas, liver, and kidney at 12 hours post-injection (n=3). (E) Real-time PCR analysis of anti-inflammatory markers Arg-1 (left) and IL-10 (right) at 120 hours after renal ischemia-reperfusion injury (IRI). Reproduced with permission from Ref.80 Copyright © 2021 American Chemical Society.

Polymeric microparticles form small spherical structures by dissolving or dispersing drugs within polymer materials. Because of their controlled and sustained-release properties and prolonged local effects, they show distinct advantages in maintaining drug delivery and prolonging half-life.¹¹² A novel functional microsphere system, Gelatin Methacryloyl–Chondroitin Sulfate–Interleukin-1 Receptor Antagonist (GelMA-CS-IL-1Ra), consists of Gelatin Methacryloyl (GelMA) and Chondroitin Sulfate Methacrylate (ChSMA). The porous architecture and negative charge of chondroitin sulfate enable dual loading of IL-1Ra with 20% efficiency, corresponding to a physiological dose of ~400 µg per milligram of matrix, while electrostatic interactions prolong the release duration. The microspheres release 30% of IL-1Ra on the first day, followed by a stable daily release of 3–5% from day 2 to day 20, maintaining a local concentration above 50 ng/mL for over 14 days, with a cumulative release of 68.2%. Evaluated in an in vivo rat model, GelMA-CS-IL-1Ra markedly suppresses pro-inflammatory mediators, reducing IL-1β protein expression by 80% and Cyclooxygenase-2 (COX-2) mRNA expression by 65%. The drug shows a half-life exceeding 7 days, no systemic toxicity, and high biocompatibility.⁸³ Another IL-1Ra-loaded microsphere system based on dextran and Poly(lactic-co-glycolic acid) (PLGA) serves as a novel anti-inflammatory formulation. In this system, dextran acts as the IL-1Ra carrier, PLGA provides the microsphere matrix, and polyvinyl alcohol (PVA) functions as the emulsifier. Researchers use an improved solid–oil–water (S/O/W) method specifically to avoid protein denaturation and maintain the therapeutic potency of IL-1Ra. The IL-1Ra-loaded dextran/PLGA microsphere system sustains IL-1Ra release for up to 56 days, reaching a cumulative concentration of 22.5 μg/mL. It demonstrates strong anti-inflammatory effects in vitro models of periodontal inflammation, reducing IL-1β by 82.1%, IL-6 by 70.1%, and TNF-α by 57.4%. Within the therapeutic concentration range, the microspheres display no significant cytotoxicity and demonstrate excellent biocompatibility, supporting an effective and sustained therapeutic strategy.⁸⁴ Injectable microparticles (MPs) for IL-1Ra delivery also represent a feasible approach. In this system, mineral-coated MPs incorporate IL-1Ra in solution to form mineral-coated IL-1Ra MPs for localized tissue delivery. Evaluated in a healing rat medial collateral ligament (MCL) injury model, on day 7, the IL-1Ra concentration reaches 0.71 pg/μg protein, which is markedly higher than the 0.12 pg/μg protein observed in the soluble IL-1Ra group, and the therapeutic effect lasts for 14 days. IL-1Ra MPs significantly reduce inflammatory cytokine levels in vivo, decreasing IL-1α by 72.9% and IL-1β by 52.4%. The mineral coating prevents chronic inflammation and foreign body reactions, and the formulation maintains excellent biocompatibility.⁸⁵

Hydrogels are three-dimensional polymer networks with high water content. Their physical similarity and mechanical compatibility with biological tissues make them advantageous for tissue engineering applications.¹¹³ The Interleukin-1 Receptor Antagonist Chitosan/β-Glycerophosphate/Gelatin Thermosensitive Hydrogel (IL-1Ra CS/β-GP/Gel) represents a novel temperature-sensitive hydrogel composed of chitosan (CS), β-glycerophosphate (β-GP), and gelatin at 37 °C. Specifically designed based on the physiological requirement of maintaining local therapeutic concentrations, this system is loaded with IL-1ra at a dose of 50 ug/mL.Beyond merely controlling release rates, this hydrogel effectively maintains the biological activity of the loaded drug. To achieve effective local concentrations (approximately 10 ug/mL as validated in vitro) and sustain them within the periodontal pocket, While it provides an initial rapid release during the first three days, the release rate stabilizes, with a half-life extending up to 21 days and a cumulative release of 83.23%. Evaluated in a diabetic periodontitis rat model, the hydrogel shows no cellular or tissue toxicity, supports long-term application, and exhibits strong anti-inflammatory effects by reducing IL-1β by 33.3%, IL-6 by 56%, and TNF-α by 51.6%.⁸⁶ The Goto-Kakizaki Pluronic F-127 Thermosensitive Gel Delivery System (GK-PF127) also serves as a thermosensitive hydrogel. PF127 functions as the core material and encapsulates IL-1Ra. The formulation remains liquid at room temperature, facilitating injection, and transforms into a hydrogel in vivo to protect IL-1Ra. The PF127 hydrogel system provides therapeutic efficacy for up to 24 hours, extends the drug half-life to 12.53 hours, and maintains high biocompatibility. The formulation achieves a 60% inhibition of IL-6, demonstrating a significant anti-inflammatory effect.⁸⁷

Novel functionalized carriers enable multifunctional and synergistic therapeutic effects. Among them, the Interleukin-1 Receptor Antagonist–loaded Gingival Margin–derived Mesenchymal Stem/Progenitor Cells in Hyaluronic Acid–based Synthetic Extracellular Matrix (IL-1Ra/G-MSCs/HA-sECM) serves as a stem-cell–combined carrier. This system uses HyStem-HP hydrogel as the scaffold and co-loads IL-1Ra with Gingival Margin–derived Mesenchymal Stem/Progenitor Cells (G-MSCs). Beyond merely acting as a physical depot, the true added value of this system lies in its ability to provide a protective niche that preserves the biological activity of IL-1Ra. Specifically designed based on the physiological levels of target cytokines, the formulation achieves a local concentration of 1000 ng/mL, which is approximately 10-fold higher than the endogenous IL-1β levels observed during the acute inflammatory phase. The formulation releases 50% of the drug rapidly within the first 1–2 days, followed by a slow release of the remaining portion from days 3 to 10, reaching a plateau thereafter and effectively suppressing chronic inflammation. Evaluated in a periodontitis model in miniature pigs, after 24 hours of drug loading, the G-MSCs maintain a survival rate of 92.3%, demonstrating excellent biocompatibility. The activity of matrix metalloproteinase-9 (MMP-9) decreases by 70.1%, and TNF-α expression decreases by 76.4%, indicating strong therapeutic potential.⁸⁸ Another system, Interleukin(IL)-1 Receptor Antagonist/recombinant human Bone Morphogenetic Protein-2/Collagen–Hydroxyapatite (IL-1Ra/rhBMP-2/CHA), functions as a growth factor–synergistic platform. It uses a collagen–hydroxyapatite (Collagen–Hydroxyapatite) scaffold as the carrier and combines IL-1Ra with recombinant human bone morphogenetic protein-2 (rhBMP-2). The system exhibits an initial burst release, reaching its peak within several hours, followed by a gradual decrease sustained for up to 7 days, successfully overcoming the rapid degradation typical of free biologics. It suppresses IL-1β–induced inflammatory responses and maintains an IL-1Ra/IL-1β ratio greater than 10, thereby blocking IL-1β signaling. Furthermore, when evaluated in a weight-bearing rat femoral defect model, the system avoids bone resorption caused by high doses of rhBMP-2, providing better safety. This formulation supports immunomodulation as an adjuvant strategy to enhance the efficacy of growth factor–based therapy.⁸⁹

Nanomaterial-Based Therapeutic Strategies for Directly Inhibiting IL-1 Production

Nanomaterials exhibit multifaceted regulatory potential in the suppression of IL-1 signaling, owing to their distinctive physicochemical characteristics.Transition metal–based nanozymes such as Mo₃Se₄, CeO₂, and Fe₃O₄ reduce oxidative stress by eliminating reactive oxygen species (ROS), thereby indirectly downregulating NLRP3 inflammasome activation and decreasing IL-1β production. Bioactive glass (BG) and metal–organic frameworks (MOFs) further modulate inflammatory pathways by influencing NF-κB and MAPK signaling, which suppresses the transcription of pro-inflammatory cytokines and limits the expression of IL-1 family members.In addition to these anti-inflammatory effects, several nanomaterials contribute to epithelial regeneration and preservation of intestinal barrier integrity, providing structural support for effective IL-1 pathway inhibition.

Natural polysaccharides and proteins, which contain various reactive groups can interact with other materials through electrostatic forces, hydrogen bonding, and Schiff base reactions. These interactions help the fabrication of nanomaterials, which are nontoxic and highly biocompatible.¹¹⁴ Similarly, protein-based polymers, typically derived from natural tissues, exhibit favorable biocompatibility and biodegradability. They undergo natural degradation after drug delivery, thereby minimizing the accumulation of byproducts.¹¹⁵ In the future, overcoming biological barriers to improve drug encapsulation and delivery efficiency, as well as employing advanced technologies to construct complex structures, may create new opportunities for drug production.¹¹⁶

Pomegranate Peel Extract–Loaded Nanoparticles (PPE-NPs) were developed by integrating polyphenol-rich Pomegranate Peel Extract (PPE) into a chitosan and sodium tripolyphosphate solution. This nanoparticulate system significantly enhances the potential of PPE as a therapeutic strategy for IBD. PPE-NPs protect the compounds from degradation by neutrophil transcytosis-associated ligand (NTAL), thereby extending the shelf life of unstable bioactives while enabling targeted delivery, controlled release, and improved therapeutic outcomes.⁹⁰ In intestinal tissues, levels of TNF-α, IL-1β, CXCL-9, CXCL-10, and nitric oxide (NO) decrease after PPE-NP treatment. Since low concentrations of NO in endothelial cells show anti-inflammatory activity, this reduction is beneficial. As the concentration of PPE-NPs increases, IL-1β levels decrease proportionally, reaching a 56.2% reduction at 150 mg/kg, which approximates the normal physiological level.¹¹⁷

To further enhance carrier responsiveness and achieve synergistic therapeutic effects, researchers designed more complex composite carrier systems. Chitosan-Coated MNS-Loaded DMPG/β-Sitosterol–Sinapic Acid Nanoliposomes (C@MNS@DMBe-S) exhibit enzyme- and pH-responsive targeted release characteristics.¹¹⁸ This system, denoted as C@MNS@DMBe-S, combines three active pharmaceutical ingredients—3,4-Methylenedioxy-β-nitrostyrene (MNS), Sinapic Acid, and β-Sitosterol—with 1,2-Dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) and chitosan as carrier materials. By inhibiting NLRP3 activation, the formulation reduces the release of IL-1β and IL-18, thereby mitigating inflammation. It also targets the NLRP3 signaling pathway to promote mucosal healing and downregulate NF-κB expression at inflammatory sites, while upregulating TGF-β levels, which reach 2.2-fold higher than baseline, to stimulate epithelial regeneration.⁹¹

For classic anti-inflammatory agents such as curcumin, which exhibit poor water solubility and low thermal stability, researchers employed polysaccharide–protein composite carriers. The Curcumin-Loaded Biopolymeric Nanocomposite (CZNH) combines curcumin with a core matrix composed of zein (corn prolamin), sodium caseinate, and hyaluronic acid. Compared with free curcumin, the CZNH nanocomposite demonstrates superior thermal stability and solubility, which translates into significantly enhanced bioavailability and a prolonged half-life in the challenging intestinal environment. By scavenging reactive oxygen species (ROS), CZNH blocks upstream activation of the NLRP3 inflammasome, thereby suppressing caspase-1 activation and reducing the cleavage of pro–IL-1β. The CZNH nanocomposite significantly decreases pro-inflammatory cytokine levels, reducing IL-1β by 23.2% and inhibiting TNF-α by 33.7%, which is approximately twice the effect of free curcumin.⁹²

Combining polysaccharides with hydrogels improves the efficiency of drug delivery. The Andrographolide/Carbon Monoxide Donor-loaded Nanoparticles (AG/CORM-2@NP) system was fabricated using poly(lactic-co-glycolic acid) (PLGA) and its PEGylated derivative, poly(lactide-co-glycolide)-b-poly(ethylene glycol)-maleimide, as carrier materials. This nanoparticle formulation encapsulated AG/CORM-2 and was embedded into a chitosan/alginate hydrogel, which exhibited good biocompatibility, sustained-release behavior, and biodegradability, enabling oral administration. AG/CORM-2@NP exerted anti-inflammatory effects by reducing the excessive production of nitric oxide (NO) and downregulating pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Specifically, IL-1β decreased by approximately 70%, and IL-6 decreased by about 69%, demonstrating effective inflammation suppression.⁹³

To deliver living therapeutics, researchers developed Bacillus amyloliquefaciens nanoparticles (BANPs). BANPs consisted of Bacillus amyloliquefaciens encapsulated in chitosan and sodium alginate nanoparticles, which enhanced probiotic survival, ensured delivery to the target site, and prolonged circulation time in vivo. BANPs inhibited the NF-κB signaling pathway, blocked IL-1β transcriptional activation, and reduced the levels of IL-1β, TNF-α, and IL-6. They also suppressed MAPK phosphorylation and reduced AP-1 activation, thereby lowering IL-1β and TNF-α production. In colon homogenates, BANPs treatment decreased IL-1β levels by 65% compared with the DSS group, while TNF-α and IL-6 levels declined by 33.3% and 80%, respectively.⁹⁴

Surface modification of base nanodispersions with natural polysaccharides further optimized both carrier performance and therapeutic outcomes. Pectin–Zein–Stigmasterol nanodispersions (ZPNs) were synthesized by combining stigmasterol-loaded zein nanoparticles (ZNs) with pectin solution. The pectin coating improves the stability, controlled-release properties, and therapeutic efficacy of the ZNs by preventing early degradation and prolonging the localized half-life of stigmasterol. Given that pro-inflammatory cytokines in acute colitis typically reach high physiological concentrations, specifically colonic tissue levels of IL-6 and TNF-α determined to be approximately 95.7 and 368.6 pg mL⁻¹ respectively. Evaluated in an acute colitis mouse model, ZPNs inhibites the NF-κB signaling pathway by preventing NF-κB p65 nuclear translocation, thereby reducing cytokine secretion. At the mRNA level, pro-inflammatory mediators were downregulated, with COX-2 decreasing by 39.7%, Colony stimulating factor 1 (CSF-1) by 79.96%, IL-6 by 80.5%, and TNF-α by 54.65%.⁹⁵

To achieve precise drug release at intestinal inflammation sites, researchers designed a targeted system responsive to intestinal enzyme degradation. Taurine-loaded chitosan–pectin nanoparticles (Tau-CS-PT-NPs) were fabricated using chitosan and pectin as carrier materials, crosslinked with sodium tripolyphosphate (STPP) to encapsulate taurine. This formulation achieved site-specific release through enzymatic degradation of pectin and chitosan by gut microbiota, protecting taurine from gastric acid and maintaining its bioactive structure. At inflammatory sites, taurine reacted with HOCl to form taurine chloramine (Tau-Cl), which inhibited NF-κB activation and reduced nuclear translocation of the NF-κB p65 subunit, thereby significantly decreasing IL-1β gene transcription. In the Tau-CS-PT-NPs group, colonic IL-1β levels were 62% lower than those in the model group.⁹⁶

Liposomes and lipid-based nanocarriers, owing to their physiological lipid structures, effectively enhance drug absorption and biocompatibility. They improve the solubility of hydrophobic drugs, enable targeted release, and provide a practical formulation platform for encapsulating bioactive compounds to enhance oral bioavailability.¹¹⁹ The Chrysin-loaded gallic acid–glycerol monostearate conjugate-based hydrogel (CR@GA-GMS) hydrogel (chrysin-loaded gallic acid–glycerol monostearate conjugate-based hydrogel) was synthesized by covalently conjugating gallic acid (GA) with glyceryl monostearate (GMS), an FDA-approved excipient, to form a GA–GMS conjugate that self-assembled into a prodrug carrier. This system further loaded chrysin (CR) with a drug loading content of 8.2% and enabled local release concentrations reaching ~25 µg/mL in vitro, achieving synergistic therapy with GA. The hydrogel exhibited inflammation-targeting adhesion, local high-concentration release, and multi-pathway synergistic therapeutic effects for efficient local treatment of IBD. CR blocked the interaction between hypoxia-inducible factor 1 alpha (HIF-1α) and p300/CREB-binding protein (CBP), reducing HIF-1α protein levels by 50% and indirectly suppressing NF-κB nuclear translocation, which downregulated TNF-α and IL-6 transcription. GA directly scavenged mitochondrial reactive oxygen species (ROS) and disrupted the ROS–thioredoxin-interacting protein (TXNIP)–NLRP3 activation axis, thereby inhibiting NLRP3 activation and reducing IL-1β and IL-18 levels. Evaluated in a DSS-induced ulcerative colitis mouse model, compared with the DSS group, CR@GA-GMS hydrogel treatment markedly downregulated TNF-α and IL-1β expression and reduced nitrite and myeloperoxidase (MPO) activity.⁹⁷ Building on the inhibition of inflammatory signaling, researchers designed a lipid-based “bomb effect” nanosystem to further enhance therapeutic precision. The lipid-based “bomb effect” nanosystem consisted of a core composed of chitosan–guanidinate–carbon dioxide (CG–CO₂), small interfering RNA targeting CD98 (siCD98), and the Annexin A1 mimetic peptide Ac2-26(Ac2-26), with a shell made of poly(lactic-co-glycolic acid) (PLGA) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Crucially, this lipid shell provided a protective shield to preserve the biological activity of the fragile siCD98 against enzymatic degradation.

This system downregulated CD98 gene expression via siCD98, subsequently reducing the pro-inflammatory cytokines TNF-α and IL-1β. TNF-α levels decreased by 44.4%, and IL-1β levels by 46.9%, indicating a pronounced anti-inflammatory effect.⁹⁸

Inorganic nanomaterials, or nanozymes, are enzyme-mimicking nanostructures capable of directly scavenging reactive oxygen species (ROS) or replicating enzymatic activity to modulate inflammatory responses at extremely low doses. The development of nanozymes with enhanced catalytic activity and stability, together with elucidation of their catalytic mechanisms to broaden therapeutic applications, represents a major direction for future research in nanozyme-based therapy.¹²⁰ Similarly, traditional BG also contributes to the modulation of inflammatory responses. Composed of SiO₂, CaO, and P₂O₅, BG features controllable multilevel structures and a synergistic silicon/calcium regulation effect. It suppresses inflammation by inhibiting activation of the Toll-like receptor 4 (TLR4)/MyD88/NF-κB signaling pathway, thereby reducing expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Evaluated in a DSS-induced colitis rat model, the 58SBG (1/20) formulation reduced IL-6 by 46.2% and TNF-α by 51.8%.⁹⁹ Meanwhile, polyethylene glycol-modified Mo₃Se₄ nanoflakes (PMNFs) have shown remarkable anti-inflammatory potential. These nanoflakes, composed of molybdenum selenide (Mo₃Se₄) and functionalized with polyethylene glycol (PEG 6000), exhibit strong antioxidant capacity and enhanced stability. Specifically, given that the local pathological concentrations of pro-inflammatory cytokines reach approximately 8000 pg/mL for IFN-β and 4000 pg/mL for IL-1β in the colon tissues. PMNFs inhibit TLR4-mediated NF-κB activation, resulting in decreased levels of the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and IFN-β. Specifically, IFN-β decreased by 48.2%, IL-1β by 68.6%, IL-6 by 51.1%, and TNF-α by 51.1%.¹⁰⁰ Finally, Acacia saligna Butanol Extract-Assisted Silver Nanoparticles (ASBE–Ag-NPs) were synthesized by reducing AgNO₃ using the butanol extract of Acacia saligna (ASBE). These inorganic nanoparticles exhibited high bioavailability and targeting capacity, effectively overcoming the rapid clearance typically associated with free extracts. Tested in a preclinical acetic acid-induced ulcerative colitis rat model, The formulation inhibited COX-2 expression and reduced prostaglandin E₂ (PGE₂) levels, thereby blocking PGE₂-mediated IL-1β and TNF-α production. As a result, pro-inflammatory cytokine levels returned to near-normal values, with a COX-2 inhibition rate of approximately 65%.¹⁰¹

Exosomes are cell-derived nanovesicles that transfer exogenous biomolecules, including proteins, mRNA, microRNA (miRNA), and lipids, to recipient cells. They exhibit natural targeting ability and low immunogenicity. Consequently, these naturally derived nanocarriers have been employed as drug delivery vehicles to transport specific therapeutic agents into target cells.¹²¹

Sophora flavescens-derived exosome-like nanovesicles carrying CX5461 (SFELNVs@CX5461) were developed by encapsulating CX5461 into SFELNVs, forming an orally stable and highly targeted formulation that overcomes the limitations of intravenous administration. SFELNVs@CX5461 suppressed the NF-κB signaling pathway, downregulated TNF-α and IL-6 expression, and inhibited Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation, thereby blocking IFN-γ–driven M1 macrophage polarization. Evaluated in a DSS-induced colitis mouse model, compared with the UC group, IL-6 protein levels decreased by 60%, and IL-1β concentrations were reduced by 65% in the SFELNVs@CX5461-treated group.¹⁰²

Among cell-derived nanocarriers, Akkermansia muciniphila-derived Extracellular Vesicles (Akk EVs) exhibit unique biological functions. These vesicles, originating from A. muciniphila and bacterial extracellular vesicles (BEVs), may promote the growth of beneficial gut microbiota through membrane fusion, thereby restoring intestinal microbial balance.¹²² Akk EVs assisted in repairing and maintaining mucosal layer thickness and upregulated the expression of barrier-associated molecules such as zonula occludens-1 (ZO-1) and Mucin 2 (MUC2), strengthening the intestinal physical barrier. Evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model, compared with the DSS group, Akk EVs significantly reduced pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, with IL-6 levels decreasing from 65 pg/mL to 50 pg/mL—a 23% reduction.¹⁰³

Polygoni orientalis L (POL)-derived exosome-like nanoparticles (PELNs) were isolated and purified from Polygoni orientalis L. (POL). These nanocarriers demonstrate an important therapeutic advantage by maintaining the bioactive structure of POL components under harsh gastrointestinal conditions, enabling site-specific targeting to inflamed tissues. PELNs activated the aryl hydrocarbon receptor (AhR) in conventional CD4⁺ T cells, downregulated Zinc finger and broad-complex, tramtrack, and bric-a-brac domain-containing protein 7B (Zbtb7b) expression, and reprogrammed these cells into double-positive CD4⁺CD8⁺ T cells, thereby reducing pro-inflammatory cytokine production. Evaluated in DSS-induced and IL-10−/− mice colitis models, compared with the DSS control group, the levels of IL-6, IL-12, IL-1β, and TNF-α significantly decreased, while IL-10 levels markedly increased.¹⁰⁴

Among food-derived nanocarriers, milk-derived extracellular vesicles (mEVs) have attracted considerable attention due to their industrial scalability. mEVs isolated from milk display high stability, resistance to digestive enzymes, broad availability of raw materials, and low production costs, effectively maintaining the biological activity of therapeutic agents and enhancing their oral bioavailability, making them suitable for large-scale manufacturing. mEVs inhibit NF-κB nuclear translocation by preventing IκBα degradation, thereby reducing IL-1β expression. They also suppress p38 and JNK overactivation and modulate extracellular signal-regulated kinase (ERK) signaling to attenuate AP-1 transcriptional activity, ultimately decreasing downstream inflammatory cytokine levels. Demonstrated in an in vitro model of intestinal inflammation, Treatment with 10¹⁰ mEVs reduced IL-1β expression by approximately 65%, and IL-17 levels returned to near-baseline values following mEV administration.¹⁰⁵

Hydrogels and composite scaffold systems consist of three-dimensional hydrophilic polymer networks and serve as promising biomaterials that mimic biological tissue structures while enabling localized drug delivery. Because they sustain drug release and protect drugs from degradation, researchers have widely applied hydrogels in tissue engineering and inflammation therapy. Their capacity to modulate cellular responses and signaling events further underscores their potential for future biomedical applications.¹²³ In studies of composite hydrogel-based carriers, researchers have embedded nanoparticles within microspheres to integrate the advantages of multiple delivery systems. They fabricated Magnolol@Chondroitin Sulfate-Zein Nanoparticles (Mag@CS-Zein NPs) using DSS, magnolol (Mag), zein, chondroitin sulfate (CS), carboxymethyl cellulose (CMC), sodium alginate, and xanthan gum. This design integrates the targeting ability of nanoparticles with the protective function of microspheres, achieving cascade drug delivery, with a physiologically relevant oral dose of 10 mg/kg, that significantly enhances the bioavailability of magnolol compared to the free drug. The formulation modulates theMag@CS-Zein NPs MAPK, NF-κB, and peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathways, regulates intestinal inflammatory cytokines, and upregulates the tight junction proteins ZO-1 and occludin to promote colonic mucosal barrier repair. In an in vivo UC mouse model, treatment with 5 μm Mag@CS-Zein NPs reduced IL-1β by 25.7%, TNF-α by 22.5%, and IL-6 by 62.5%, effectively relieving inflammation.¹⁰⁶ Beyond composite carriers, researchers have developed stimuli-responsive hydrogel systems that represent significant advances in drug delivery. For example, they created an enzyme-responsive hydrogel (ER-hydrogel) using glycerol monostearate as the main material and applied a heat–cooling process to encapsulate the glucocorticoid budesonide. The ER-hydrogel exhibits excellent sustained-release behavior, releasing only 25% of the drug within 15 days and achieving a drug-loading efficiency of 97%. At inflammatory sites, the hydrogel releases budesonide to block the NF-κB signaling pathway and suppress IL-1β gene transcription, which lowers IL-1β and TNF-α levels by 60% and 58%, respectively, producing a strong anti-inflammatory effect.¹⁰⁷ The preparation and anti-inflammatory mechanism of Mag@CS-Zein NPs are detailed in Figure 5.

Figure 5.

Anti-inflammatory mechanism of nanoparticle-embedded microspheres (Mag@CS-Zein NPs). (A) Preparation and targeted delivery of Mag@CS-Zein NPs. (B) Microscopic images of Mag@CS-Zein NPs in simulated digestive fluid. (C) In vitro release profiles of free Mag, Mag@CS-Zein NPs, and Mag@CS-Zein NPs-in-MPs. (D) Effects of Mag@CUL-Zein NPs and Mag@CS-Zein NPs on IL-1β secretion in NCM460 and RAW 264.7 cells. (E) Representative H&E and PAS staining of colonic tissues. (F) Inflammatory cytokine levels (TNF-α, IL-1β, IL-6, IL-10). *p < 0.05 vs Ctrl; Δp < 0.05 vs other groups. Reproduced with permission from Ref.¹⁰⁶ Copyright © 2021 American Chemical Society.

Gut microbiota dysbiosis serves as a primary cause of ulcerative colitis (UC). Live bacteria and probiotic delivery systems help treat IBD by reshaping and restoring the intestinal microbial community.¹²⁴ Bifidobacterium breve, Bacillus coagulans, and Lactobacillus plantarum-loaded Nanoparticles (BBLNPs) combine three core probiotics — Bifidobacterium breve, Bacillus coagulans, and Lactobacillus plantarum — with sodium alginate and chitosan to form a protective nanocarrier matrix. This encapsulation markedly enhances probiotic viability under simulated gastrointestinal conditions and alleviates intestinal inflammation through multiple mechanisms, effectively maintaining their high biological activity and extending their functional half-life compared to non-encapsulated probiotics. Specifically, after 90 minutes in simulated gastrointestinal juice, the three constituent strains within BBLNPs maintained high viability with counts of 8.8×10⁸, 9.3×10⁸ and 7.2×10⁸ CFU/mL, respectively, which was up to two orders of magnitude higher than the free probiotics. In a preclinical DSS-induced rat model, BBLNPs downregulate NLRP3 mRNA expression, inhibit the conversion of pro-IL-1β to active IL-1β, and promote macrophage polarization toward the anti-inflammatory M2 phenotype. They also increase the proportion of Treg cells while suppressing Th17 responses. Consequently, BBLNPs significantly reduce TNF-α and IL-6 levels, achieving up to 63.7% inhibition of TNF-α expression.¹⁰⁸ Beyond BBLNPs, extracellular vesicles derived from Lactobacillus reuteri (LrEVs) also regulate intestinal immune balance. Acting through the “probiotic–vesicle–immune cell” axis, LrEVs deliver bioactive signals via nanoscale vesicles to precisely coordinate pro- and anti-inflammatory responses among multiple intestinal immune cell types. Specifically, LrEVs restore the local intestinal concentrations of pro-inflammatory cytokines from pathophysiological highs such as TNF-α at approximately 25 U/mg protein toward homeostasis. LrEVs modulate macrophage function by inhibiting NF-κB signaling, thereby reducing pro-inflammatory cytokine production and enhancing anti-inflammatory activity. Compared with controls, TNF-α decreased by 60%, IL-1β by 72.2%, and IL-6 by 50%, whereas IL-10 expression increased fivefold.¹⁰⁹ The anti-inflammatory mechanism and key experimental findings of LrEVs are illustrated in Figure 6.

Figure 6.

Anti-inflammatory mechanism of LrEvs. (A) Procedure for the isolation and purification of bacterial extracellular vesicles. (B) Activity of the NF-κB p65 transcription factor in the nuclei of HD11 cells treated under indicated conditions. HD11 cells (5 × 10⁵ cells/mL) were pretreated with PBS or LrEVs (10 μg/mL) for 12 h, followed by stimulation with PBS or Lipopolysaccharide (LPS) (1 μg/mL) for 12 h. (C) LrEVs inhibit LPS-induced gene expression of pro-inflammatory mediators, including the pro-inflammatory cytokine genes TNF-α, *IL-1β*, *IL-6*, and *IL-17*, as well as the chemokine genes *IL-8* and * macrophage inflammatory protein-1 beta (MIP-1β)*. (D) Representative scanning electron microscopy (SEM) image of LrEvs. (E) Representative transmission electron microscopy (TEM) image of LrEvs. (F) Schematic diagram illustrating the mechanism by which LrEV-mediated bacterium–host crosstalk drives intestinal immune homeostasis against pathogen-induced inflammation in a chicken model. This figure is adapted from the article by Rujiu Hu, Hua Lin, et al;¹⁰⁹ the original figure is licensed under CC BY 4.0. https://jasbsci.biomedcentral.com/articles/10.1186/s40104-020-00532-4.

Discussion

This review elucidates the immunopathogenic mechanisms of the interleukin-1 (IL-1) cytokine family in IBD and summarizes the recent progress in nanomaterial-based IL-1–targeted therapeutic strategies. The IL-1 signaling pathway serves as a crucial bridge linking innate and adaptive immunity. Traditional biologics such as anakinra and canakinumab exhibit therapeutic potential but remain limited by low bioavailability and insufficient intestinal targeting. Nanocarriers enable precise delivery and sustained release of IL-1 inhibitors, while some nanomaterials can directly suppress excessive IL-1 expression, thereby enhancing efficacy and reducing systemic side effects. The comprehensive therapeutic framework is illustrated in Figure 7. These nano-enabled strategies not only establish a solid theoretical foundation for developing precise, efficient, and safe IBD therapies but also provide valuable guidance for future clinical translation and rational drug design.

Figure 7.

Integrated overview of nanomaterial-based strategies targeting the IL-1 axis in inflammatory bowel disease. Pathogenic processes in IBD, including epithelial barrier disruption, microbial dysbiosis, oxidative stress and inflammasome activation, promote excessive activation of IL-1-associated inflammatory pathways. Multiple nanomaterial-based platforms, including lipid-based nanocarriers, polymeric nanoparticles, hydrogels, exosomes, inorganic nanozymes and bacteria-based delivery systems, can be engineered to achieve site-specific accumulation and inflammation-responsive release triggered by pH, reactive oxygen species (ROS), enzymes or other features of the inflammatory microenvironment. These platforms may exert therapeutic effects through several mechanisms, including blockade of IL-1 ligand–receptor interactions, delivery of therapeutic cargos such as siRNA, mRNA or antibodies, inhibition of pro-inflammatory signalling pathways such as NF-κB and MAPK, and scavenging of ROS. Collectively, these strategies may help restore intestinal barrier integrity, rebalance mucosal immunity, improve microbiota homeostasis and reduce intestinal inflammation.

Despite remarkable advances in elucidating the pathogenesis of IBD, current clinical management remains largely symptomatic rather than curative. IL-1β plays a pivotal upstream role in this process. Excessive IL-1 signaling amplifies inflammatory cascades through NF-κB and MAPK pathways, disrupts epithelial tight junctions, promotes T helper 17 (Th17) polarization, and suppresses regulatory T cell (Treg) differentiation, ultimately leading to persistent mucosal injury.¹²⁵ Although existing IL-1–targeted therapeutics are mechanistically well grounded, their clinical efficacy is limited. For example, anakinra has shown a suboptimal clinical response in acute severe ASUC. This is primarily attributed to its extremely short biological half-life and the inability of systemic administration to achieve sufficiently high local drug concentrations in the severely inflamed mucosa to counteract the massive cytokine burst. Systemic administration often induces off-target effects and rapid clearance, resulting in insufficient drug accumulation at intestinal lesions.¹²⁶ Moreover, the redundancy of cytokine networks implies that blockade of a single IL-1 ligand may trigger compensatory signaling via other IL-1 family members (such as IL-18, IL-33, and IL-36), thereby attenuating therapeutic efficacy.¹²⁷ Nanomaterials offer an effective platform to overcome these pharmacokinetic and pharmacodynamic limitations in IL-1–based therapy.

Compared with traditional systemic biologics, nanocarriers allow spatiotemporal control, targeted accumulation, and controlled release within inflamed intestinal sites. Polysaccharide- and protein-based nanoparticles, liposomal systems, and polymeric microspheres can encapsulate IL-1 receptor antagonists or monoclonal antibodies, protecting them from enzymatic degradation and prolonging their half-life.¹²⁸ However, compared to conventional microparticles, nano-sized carriers demonstrate unique size-dependent advantages, such as superior mucus penetration and deeper accumulation within inflamed mucosal cells. For instance, chitosan-coated lipid nanoparticles and poly(lactic-co-glycolic acid) (PLGA) microspheres can provide sustained release of IL-1 receptor antagonist (IL-1Ra) for up to 14–56 days, significantly reducing IL-1β and TNF-α expression in colitis models.¹²⁹ Similarly, sphingomyelin nanosystems loaded with anakinra exhibit enhanced intracellular delivery and prolonged bioactivity compared with free drug formulations.⁷⁹ Collectively, these findings demonstrate that nanocarrier-mediated delivery of IL-1 inhibitors achieves higher local drug concentrations, longer therapeutic windows, and lower systemic toxicity. Moreover, redox- or pH-responsive hydrogels serve as secondary macroscopic scaffolds to encapsulate and retain therapeutic nanoparticles, enabling on-demand release within the inflamed mucosa. Compared with free cytokine inhibitors, these nanoplatforms minimize systemic immunosuppression and facilitate integration of antioxidant, mucosal repair, or probiotic functionalities, providing multidimensional therapeutic modalities that are unattainable with conventional drugs.

In addition to serving as delivery vehicles, certain nanomaterials can directly modulate IL-1 expression by targeting upstream inflammasome activation or oxidative stress. These materials share common features. For example, molybdenum selenide (Mo₃Se₄) nanoflakes, bioactive glass, and silver nanoparticles regulate reactive oxygen species (ROS), restore redox homeostasis, inhibit NLRP3 inflammasome activation, and block IL-1β maturation.^100,130,131 Their high catalytic activity and structural stability allow them to exert effects at extremely low doses. The rationale for selecting these specific inorganic elements heavily depends on their unique multivalent oxidation states and nanozyme activities, whereas many other elements lack such catalytic capabilities or exhibit prohibitive heavy-metal toxicity. Furthermore, compared to traditional organic carriers—which excel in biocompatibility and drug encapsulation but lack intrinsic therapeutic activity—these inorganic nanomaterials offer superior enzymatic stability and direct immunomodulatory properties. However, their clinical translation is still hindered by potential long-term tissue accumulation, whereas organic carriers are generally fully biodegradable. Polyphenol-loaded polysaccharide nanocomposites can directly inhibit NF-κB nuclear translocation, reducing IL-1β transcription by over 50%.¹³² Bio-derived vesicles possess inherent tropism toward inflamed tissues and can endogenously modulate IL-1 production while maintaining epithelial integrity.¹³³ Regarding microbiota-modulating strategies, live probiotics (eg, BBLNPs) offer dual benefits by delivering anti-inflammatory signals and actively restoring the dysbiotic microbiome. These approaches are increasingly vital as the microbiota-immune axis dictates that specific microbial colonization triggers IL-1 production and downstream inflammatory cascades. However, their translation is hindered by strict viability requirements, unpredictable in vivo colonization, and translocation risks. Conversely, cell-free systems like LrEVs avoid viability issues and infection risks, providing a safer alternative. Yet, their application remains limited by complex isolation, low yields, and unstandardized purification. Therefore, nanomaterials not only function as carriers but may also exert intrinsic immunomodulatory activity. Future designs incorporating IL-1–responsive groups, redox-sensitive linkages, or inflammasome inhibitors could enable nanomaterials to dynamically adapt to the inflammatory microenvironment, providing a rational blueprint for next-generation IBD nanotherapies.

Nevertheless, IL-1–targeted nanotherapeutics face several challenges in clinical translation. First, because the IL-1 pathway lies upstream in inflammatory signaling, systemic blockade may increase susceptibility to infection or induce secondary inflammation through compensatory cytokine activation.¹³⁴ Additionally, nanocarriers may elicit complement activation or alter mucosal immunity, and their long-term local safety remains insufficiently characterized. Second, the harsh gastrointestinal environment—including acidity, digestive enzymes, and mucus barriers—limits effective drug concentration and retention at lesion sites, necessitating optimization of nanostructures, such as multilayered shells or stimuli-responsive materials, to improve stability and delivery efficiency. Furthermore, complex multicomponent systems (eg, exosome-based or hybrid responsive materials) are difficult to standardize and often show batch variability in particle size, drug loading, and purity, which hinders translational consistency. Commonly used acute colitis models (eg, DSS or 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis) also fail to fully recapitulate the chronic and relapsing features of human IBD, resulting in discrepancies between preclinical efficacy and clinical outcomes. Finally, IBD exhibits pronounced heterogeneity, as differences in subtype, lesion location, and gut microbiota composition affect IL-1 dependence and therapeutic response.

Despite the therapeutic potential of nanomedicine for inflammatory bowel disease (IBD), its clinical translation remains hindered by several fundamental challenges. The physiological heterogeneity of the human gastrointestinal tract—characterized by variable pH, mucus thickness, and disease-specific protein corona formation—often renders successful rodent-based outcomes non-transferable to clinical settings. Moreover, current preclinical models primarily reflect acute immune responses and cannot entirely replicate the chronic, relapsing pathology of human IBD. While this discrepancy may cause variances in therapeutic efficacy, the critical role of IL-1 signaling is broadly validated in clinical studies, making the continued development of IL-1-targeted nanotherapeutics highly necessary. Furthermore, oral delivery is complicated by the paradoxical requirement for both mucoadhesion and deep tissue penetration across an inconsistently inflamed intestinal barrier. Beyond delivery efficiency, the inherent immunogenicity of nanocarriers poses a risk of provoking unintended local inflammation, while the complexity of multi-step syntheses presents substantial barriers to GMP-compliant scalability and manufacturing reproducibility. Long-term safety concerns also persist, particularly regarding tissue accumulation, chronic toxicity, and the potential for treatment-induced dysbiosis during prolonged administration. Ultimately, the lack of standardized methodological frameworks and comprehensive safety data underpins the current gap between preclinical innovation and regulatory approval for IBD nano-therapies.

Targeting IL-1 family cytokines closely associated with IBD onset and progression, this review summarizes two main regulatory strategies:(1)constructing nanocarriers to efficiently deliver IL-1 inhibitors, thereby improving pharmacokinetic profiles and targeting efficiency; and(2)exploiting the intrinsic properties of nanomaterials to directly modulate upstream IL-1 signaling or remodel the immune microenvironment. Future research should focus on the following directions: 1. Integrating drug delivery with real-time monitoring to achieve lesion visualization and precision-controlled release. 2. Employing biodegradable, low-immunogenicity materials as core components, establishing standardized safety assessment and quality control frameworks, and ensuring batch consistency and traceability through QbD and process analytical technology (PAT) approaches to accelerate clinical translation. 3. Combining patient-specific cytokine profiles, genetic features, and gut microbiome information to develop personalized nanocarriers with tunable release and targeting depth, coupled with companion diagnostics to monitor IL-1 signaling dynamics, thereby enabling individualized dosing and treatment optimization and promoting the evolution of IBD therapy toward stratified precision medicine. To ensure clarity and facilitate reading, all abbreviations used in this discussion and throughout the paper, along with their corresponding full names and definitions, are summarized in Table 3.

Table 3.

List of Abbreviations

Abbreviation	Full Term
Ac2-26	Annexin A1 mimetic peptide Ac2-26
ADA	Anti-drug antibodies
AG/CORM-2@NP	Andrographolide/Carbon Monoxide Donor-loaded Nanoparticles
AhR	Aryl hydrocarbon receptor
AIED	Autoimmune inner ear disease
Akk EVs	Akkermansia muciniphila-derived Extracellular Vesicles
ANK	Anakinra
AP-1	Activator protein 1
ASBE–Ag-NPs	Acacia saligna Butanol Extract-Assisted Silver Nanoparticles
ASUC	Acute Severe Ulcerative Colitis
ATF	Activating transcription factor
BANPs	Bacillus amyloliquefaciens nanoparticles
BBLNPs	Bifidobacterium breve, Bacillus coagulans, and Lactobacillus plantarum-loaded Nanoparticles
BEVs	Bacterial extracellular vesicles
BG	Bioactive glass
BTB	Broad-complex, Tramtrack, and Bric-a-brac
CAPS	Cryopyrin-Associated Periodic Syndrome
CBP	CREB-binding protein
CD	Crohn’s Disease
CG–CO2	Chitosan–guanidinate–carbon dioxide
ChSMA	Chondroitin Sulfate Methacrylate
CMC	Carboxymethyl cellulose
C@MNS@DMBe-S	Chitosan-Coated MNS-Loaded DMPG/β-Sitosterol–Sinapic Acid Nanoliposomes
COX-2	Cyclooxygenase-2
CPC	Cationic peptide carrier
CR@GA-GMS	Chrysin-loaded gallic acid–glycerol monostearate conjugate-based hydrogel
CS	Chitosan
CSF-1	Colony stimulating factor 1
CXCL	Chemokine (C-X-C motif) ligand
CZNH	Curcumin-Loaded Biopolymeric Nanocomposite
DAMP	Damage-associated molecular pattern
DC	Dendritic cell
DMPG	1,2-Dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol)
DOPE	1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine
DPPC	1,2-Dipalmitoyl-sn-glycero-3-phosphocholine
DSPE-PEG	1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]
DSS	Dextran sulfate sodium
EGF	Epidermal growth factor
ER-hydrogel	Enzyme-responsive hydrogel
ERK	Extracellular signal-regulated kinase
ExoCPC-IL-1RA	Exosome–Cationic Peptide Carrier–Interleukin-1 Receptor Antagonist
FMF	Familial Mediterranean fever
FNV	Fluorescent nanovector
Foxp3	Forkhead box P3
GA	Gallic acid
GelMA	Gelatin Methacryloyl
GelMA-CS-IL-1Ra	Gelatin Methacryloyl–Chondroitin Sulfate–Interleukin-1 Receptor Antagonist
GK-PF127	Goto-Kakizaki Pluronic F-127 Thermosensitive Gel Delivery System
G-MSCs	Gingival Margin–derived Mesenchymal Stem/Progenitor Cells
GMS	Glycerol monostearate
GPP	Generalized pustular psoriasis
HIF-1α	Hypoxia-inducible factor 1 alpha
HSCT	Hematopoietic stem cell transplantation
IBD	Inflammatory Bowel Disease
ICAM-1	Intercellular Adhesion Molecule 1
IFN-γ	Interferon gamma
IL-1	Interleukin-1
IL-1α	Interleukin-1 alpha
IL-1β	Interleukin-1 beta
IL-1R1	Interleukin-1 receptor type I
IL-1R2	Interleukin-1 receptor type 2
IL-1R8	Interleukin-1 receptor 8 (SIGIRR)
IL-1RAcP	Interleukin-1 receptor accessory protein
IL-1Ra	Interleukin-1 receptor antagonist
IL-1Ra CS/β-GP/Gel	Interleukin-1 Receptor Antagonist Chitosan/β-Glycerophosphate/Gelatin Thermosensitive Hydrogel
IL-1Ra/G-MSCs/HA-sECM	Interleukin-1 Receptor Antagonist–loaded Gingival Margin–derived Mesenchymal Stem/Progenitor Cells in Hyaluronic Acid–based Synthetic Extracellular Matrix
IL-1Ra/rhBMP-2/CHA	Interleukin-1 Receptor Antagonist/recombinant human Bone Morphogenetic Protein-2/Collagen–Hydroxyapatite
IL-18	Interleukin-18
IL-18BP	Interleukin-18 binding protein
IL-18Rα	Interleukin-18 receptor alpha
IL-18Rβ	Interleukin-18 receptor beta
IL-33	Interleukin-33
IL-36α	Interleukin-36 alpha
IL-36β	Interleukin-36 beta
IL-36γ	Interleukin-36 gamma
IL-36R	Interleukin-36 receptor
IL-36Ra	Interleukin-36 receptor antagonist
IL-37	Interleukin-37
IL-38	Interleukin-38
ILC	Innate lymphoid cell
ILCregs	Regulatory innate lymphoid cells
IRAK	Interleukin-1 receptor-associated kinase
JNK	c-Jun N-terminal kinase
LNPs	Lipid nanoparticles
LPS	Lipopolysaccharide
LrEVs	Lactobacillus reuteri-derived Extracellular Vesicles
MAdCAM-1	Mucosal addressin cell adhesion molecule-1
Mag@CS-Zein NPs	Magnolol@Chondroitin Sulfate-Zein Nanoparticles
MAPK	Mitogen-activated protein kinase
MCP	Monocyte chemoattractant protein
mEVs	Milk-derived Extracellular Vesicles
MIP-1β	Macrophage inflammatory protein-1 beta
MMP-9	Matrix metalloproteinase-9
MNS	3,4-Methylenedioxy-β-nitrostyrene
MOFs	Metal–organic frameworks
MPO	Myeloperoxidase
MPs	Microparticles
MUC2	Mucin 2
MyD88	Myeloid differentiation primary response 88
NALI	Poly(N-acryloyl-L-isoleucine)
NF-κB	Nuclear factor kappa B
NLRP3	NLR family pyrin domain containing 3
NO	Nitric oxide
NTAL	Neutrophil transcytosis-associated ligand
PAT	Process analytical technology
PDI	Perylenediimide
PELNs	Polygoni orientalis L.-derived exosome-like nanoparticles
PEG	Polyethylene glycol
PGE2	Prostaglandin E2
PLGA	Poly(lactic-co-glycolic acid)
PMNFs	Polyethylene glycol-modified Mo3Se4 nanoflakes
POL	Polygoni orientalis L.
PPE-NPs	Pomegranate Peel Extract–Loaded Nanoparticles
PPAR-γ	Peroxisome proliferator-activated receptor gamma
PVA	Polyvinyl alcohol
QbD	Quality-by-design
RA	Rheumatoid arthritis
RCT	Randomized controlled trial
rhBMP-2	Recombinant human bone morphogenetic protein-2
rIL-18	Recombinant IL-18
ROS	Reactive oxygen species
SFELNVs@CX5461	Sophora flavescens-derived exosome-like nanovesicles carrying CX5461
sJIA	Systemic juvenile idiopathic arthritis
siCD98	Small interfering RNA targeting CD98
SIGIRR	Single Ig IL-1-related receptor
siRNA	Small interfering RNA
SNs	Sphingomyelin nanosystems
ST2	Suppression of tumorigenicity 2
STAT1	Signal Transducer and Activator of Transcription 1
STPP	Sodium tripolyphosphate
Tau-Cl	Taurine chloramine
Tau-CS-PT-NPs	Taurine-loaded chitosan–pectin nanoparticle
TGF-β	Transforming growth factor beta
Th17	T helper 17
TIR	Toll/interleukin-1 receptor
TIR domain	Toll/Interleukin-1 Receptor domain
TLR4	Toll-like receptor 4
TNBS	2,4,6-Trinitrobenzenesulfonic acid
TNF-α	Tumor necrosis factor alpha
TRAF6	TNF receptor-associated factor 6
TRAPS	TNF receptor-associated periodic syndrome
Treg	Regulatory T cell
TXNIP	Thioredoxin-interacting protein
UC	Ulcerative Colitis
Zbtb7b	Zinc finger and BTB domain-containing protein 7B
ZO-1	Zonula occludens-1
ZPNs	Pectin–Zein–Stigmasterol nanodispersions

Conclusion

In summary, the pathological orchestration of the IL-1 cytokine family—specifically the NLRP3-mediated maturation of IL-1β and IL-18—is a fundamental driver of mucosal inflammation and epithelial barrier failure in IBD While traditional biologics have validated the therapeutic potential of IL-1 blockade, their clinical utility is frequently compromised by suboptimal pharmacokinetics and a lack of tissue-specific accumulation. This review highlights that nanotechnology represents a paradigm shift in overcoming these constraints through a dual-pronged strategy.

On one hand, sophisticated nanocarriers—engineered from polymeric, lipid-based, or bio-derived materials—provide essential spatiotemporal control over drug release. By harnessing the unique physiological cues of the inflamed gut such as pH gradients, redox shifts, and enzymatic overactivity, these platforms ensure targeted delivery of IL-1 antagonists, thereby recalibrating the Th17/Treg balance and facilitating mucosal healing. On the other hand, the emergence of inorganic nanomaterials with intrinsic biocatalytic activities, particularly nanozymes, offers a robust means to directly modulate the inflammatory microenvironment. These materials exert multimodal effects—scavenging ROS and inhibiting upstream signaling cascades—that complement traditional pharmacological approaches.

Despite these advancements, the bench-to-bedside transition of IL-1–targeted nanotherapies necessitates addressing critical translational bottlenecks. Future research must transcend simple efficacy studies in rodent models to focus on the long-term biocompatibility of nanomaterials, the standardization of large-scale manufacturing (GMP compliance), and the complex bio-interfacial crosstalk between nanoparticles and the gut microbiota. Ultimately, integrating patient-stratified cytokine profiling with “smart” stimuli-responsive nanomedicines will pave the way for a more precise, individualized, and effective therapeutic framework for patients suffering from IBD.

Funding Statement

This work was supported by the Wu Jieping Medical Foundation of China (320.6750.2024-03-62). The views expressed are those of the authors and not necessarily those of the Wu Jieping Medical Foundation of China.

Highlights

• Elucidates IL-1 mechanisms: Deciphers the immunopathogenic role of the IL-1 cytokine family linking innate and adaptive immunity in IBD.

• Targeted drug delivery: Highlights nanocarriers that overcome gastrointestinal barriers for site-specific and sustained release of IL-1 inhibitors.

• Intrinsic immunomodulation: Explores nanozymes and bioactive materials that directly suppress IL-1 production via ROS elimination and NLRP3 blockade.

• Translational barriers: Critically evaluates clinical challenges, including gastrointestinal heterogeneity, carrier safety, and manufacturing scalability.

• Precision nanomedicine: Proposes personalized nanocarriers and Quality-by-Design (QbD) strategies for the future of IBD precision therapy.

Data Sharing Statement

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

Author Contributions

Kexin Wang: Writing-original draft, Writing-review & editing, Conceptualization, Visualization. Siyan Chen: Visualization, writing-original draft, writing -review&editing. Jiaqi Zhang: Visualization, Writing-review & editing. Jiayi Du: Visualization, Writing-review & editing. Yiruo Liu: Writing-original draft, Visualization. Dong Li: Conceptualization, Supervision, writing -review & editing. Xuan Sun: Conceptualization, Funding acquisition, Funding acquisition, Project administration, writing -review&editing. Yanyan Song: Conceptualization, Funding acquisition, Project administration, writing -review & editing. All authors gave final approval of the version to be published; approved on the journal to which this artical was submitted; and agree to be accountable to the content of this article.

Kexin Wang and Siyan Chen share first authorship.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.