Hydrogels in Autoimmune Disease: From Passive Carriers to Active Immune Regulation Platforms
核心洞察
Hydrogels are evolving from passive drug carriers into active immune regulation platforms capable of reshaping the inflammatory microenvironment in autoimmune diseases.
Intelligent stimulus-responsive hydrogels enable on-demand drug release triggered by pH, temperature, ROS (搜索), and other pathological signals characteristic of autoimmune conditions.
Preclinical studies demonstrate hydrogel-based therapies can reduce pro-inflammatory cytokines, promote macrophage M2 polarization, and alleviate joint destruction in rheumatoid arthritis (搜索) models.
Hydrogels—three-dimensional crosslinked polymer networks with high water content—are undergoing a fundamental transformation in the treatment of autoimmune diseases, shifting from simple drug delivery vehicles to sophisticated platforms that actively regulate the immune microenvironment. A comprehensive review published in the International Journal of Nanomedicine maps this evolution across rheumatoid arthritis (搜索), systemic lupus erythematosus (搜索), Sjögren's disease (搜索), systemic sclerosis (搜索), multiple sclerosis (搜索), and diabetes, highlighting both remarkable preclinical progress and the significant hurdles that remain before clinical translation.
The review, which analyzed 160 articles from the Web of Science Core Collection spanning 2004 to 2025, reveals that hydrogel research in autoimmune disease is accelerating, with drug delivery emerging as the dominant application. "The core trend is evolving from 'passive carriers' to 'active regulation platforms'," the authors note, emphasizing that hydrogels are "no longer being merely a drug carrier," with their potential to reshape the inflammatory microenvironment now validated across multiple animal models.
Rheumatoid Arthritis (搜索): The Most Active Frontier
Rheumatoid arthritis (搜索) (RA) represents the most intensively studied autoimmune indication for hydrogel-based therapies. The disease, characterized by symmetrical joint inflammation leading to irreversible joint destruction, has driven innovation across multiple hydrogel strategies targeting distinct pathological mechanisms.
Macrophage-targeted approaches feature prominently. Liu et al developed a heat-sensitive injectable hydrogel loaded with dexamethasone and crocetin 1 that extended drug retention time in the joint cavity while ensuring sustained release. In arthritic rats, the formulation significantly reduced TNF-α (搜索), IL-1β, IL-6, and IL-17A levels, improved joint redness and bone erosion, and decreased thymus and spleen weight. Similarly, Wu et al engineered an injectable pH-sensitive IOK peptide hydrogel carrying methotrexate and bismuth nanosheets capable of simultaneously reducing macrophage activity and eliminating overproliferating synovial fibroblasts.
Wang et al took a different approach with a bidynamic crosslinked sodium alginate hydrogel (SPT@TPL) combining stimulus response to reactive oxygen species (ROS (搜索)) with on-demand triptolide release. In RA model rats, the hydrogel increased articular cartilage morphology, trabecular number, and bone mineral density—effects attributed to effective ROS clearance and promotion of macrophage M2 polarization.
The neutrophil extracellular trap (NET) pathway has also drawn attention. Wang et al coupled deoxyribonuclease I with oxyhyaluronic acid, crosslinked it with carboxymethyl chitosan to form an injectable hydrogel (DHY), and loaded methotrexate. In CIA mice, DHY@MTX normalized joint symptoms, produced clear articular surfaces, and decreased TNF-α (搜索) and IL-6 levels—outcomes significantly superior to individual component controls.
Perhaps most ambitiously, Cheng et al developed a nanoparticle hydrogel (NiH) loaded with cGAS inhibitor nanoparticles, targeting cell-free DNA-mediated inflammation. In CIA mice, NiH significantly reduced joint swelling, decreased serum cfDNA, TNF-α (搜索), IFN-β, and IL-12, and shifted the T-cell balance by reducing CD3+, CD4+, CD8+, and Th17 cells while increasing Treg cells.
Beyond RA: Expanding Indications
In systemic lupus erythematosus (搜索) (SLE), Huang et al demonstrated that agarose hydrogel containing anti-TNF-α (搜索) antisense oligonucleotides, injected subcutaneously into MRL/Lpr mice, aggregated in macrophages, significantly reduced TNF-α levels, inhibited lymphocyte proliferation, and alleviated lupus-like symptoms. Nie et al reported that porous adhesive particles encapsulating mesenchymal stem cells (MSCs) reduced spleen weight, anti-dsDNA antibody levels, and glomerular IgG and C3 deposition in the same model.
For Sjögren's disease (搜索), a prospective clinical study by Li et al involving 37 patients with severe dry eye found that bandage contact lenses significantly improved best-corrected visual acuity compared with autologous serum eye drops, with lower ocular surface disease index and corneal staining scores persisting six weeks after treatment discontinuation. On the preclinical side, Mu et al developed an ROS (搜索)-responsive microneedle patch loaded with cyclosporin A and epicatechin that prolonged drug action time in the lacrimal gland and inhibited Th1, Th17, and macrophage proliferation in mouse models.
In systemic sclerosis (搜索), a traditional Chinese medicine-integrated microneedle system combining triptolide, paeoniflorin, and black phosphorus nanoparticles with near-infrared light rapidly recovered damaged skin area and reduced dermal thickness in bleomycin-induced mouse models, while also reducing the liver toxicity of triptolide.
For multiple sclerosis (搜索), Thomas et al reported that hydrogel delivery of interleukin-10-treated dendritic cells improved paralysis in preclinical experimental autoimmune encephalomyelitis mice, particularly when administered near cervical lymph nodes.
Diabetes: Islet Transplantation and Wound Healing
Diabetes applications span both type 1 diabetes management and diabetic foot complications. Trinh et al prepared chitosan-insulin nanosphere composites in pH- and temperature-sensitive hydrogels that maintained steady plasma insulin levels and effectively reduced blood glucose in streptozotocin-induced diabetic mice. Nag et al found that hyaluronic acid/heparin/collagen hydrogel-mediated IL-2 delivery reduced diabetes incidence in NOD mice compared with soluble IL-2 injection.
For diabetic foot, a module combining element-dominated exosomes with an adaptive dual-network hydrogel (3D-TE-Exo) significantly enhanced vascular network formation, decreased ROS (搜索) expression, restored mitochondrial membrane potential, and transformed macrophages from M1 to M2 type through a complement-mitochondria-autophagy circuit in SD rats.
Challenges Ahead
Despite promising preclinical data, the review identifies substantial barriers to clinical translation. Long-term biocompatibility and degradability require systematic in vivo assessment, including chronic toxicity, immunogenicity, and long-term tissue compatibility of degradation products. The distribution, retention time, and cartilage interaction of hydrogels after intra-articular injection need more precise imaging verification.
A fundamental limitation is that current strategies primarily target downstream inflammatory effects rather than upstream causes. "To achieve long-term disease remission or even cure, it is necessary to move towards the induction of antigen-specific immune tolerance, which is currently still in the concept verification stage," the authors state. Standardization of antigen selection, delivery routes, and immune monitoring methods remains unresolved.
Manufacturing consistency presents another critical challenge. The immune regulatory function of hydrogels is highly dependent on microstructural consistency, and ensuring batch-to-batch stability during scale-up from laboratory preparation to large-scale production is an urgent problem.
The review concludes that multidisciplinary collaboration will be the decisive force driving hydrogel therapy toward clinical application in autoimmune diseases, with intelligent responsive hydrogels, multifunctional platforms combining drug delivery with immune regulation and tissue repair, and integration with gene and cell therapies representing the most promising future directions.