Resetting the redox-immune axis with IL-4-loaded allomelanin nanoparticles for osteoarthritis therapy

An IL-4-loaded allomelanin nanoparticle (IL-4@AMNPs) is developed. • IL-4@AMNPs scavenge ROS and reprogram macrophages toward M2 phenotype. • The nanoplatform shows sustained intra-articular retention over 144 h. • IL-4@AMNPs alleviate cartilage degradation and inflammation in OA rats. • A synergistic redox-immune modulation strategy for disease-modifying OA therapy. Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by chronic synovitis and progressive cartilage destruction, in which excessive reactive oxygen species (ROS) play a central pathogenic role. Herein, we reported the design of allomelanin-like nanoparticles loaded with interleukin-4 (IL-4@AMNPs) as a multifunctional nanoplatform. Benefiting from the intrinsic antioxidant activity of AMNPs, the system efficiently scavenges excessive ROS, while the incorporated IL-4 exerts anti-inflammatory and M2-polarizing effects. In a rat model of OA, intra-articular administration of IL-4@AMNPs markedly attenuated cartilage erosion, reduced ROS accumulation, and downregulated matrix metalloproteinase-3 (MMP-3) expression. Furthermore, IL-4@AMNPs suppressed the expression of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), restored the anti-inflammatory cytokine IL-10, and reprogrammed macrophages from the M1 toward the M2 phenotype, thereby reshaping the joint immune microenvironment. Both in vitro and in vivo safety assessments confirmed the excellent biocompatibility and systemic safety of IL-4@AMNPs. Collectively, this study demonstrated that IL-4@AMNPs disrupt the pathological interplay between oxidative stress and inflammation, achieving synergistic chondroprotection via dual ROS scavenging and IL-4-mediated macrophage reprogramming and offering a promising disease-modifying nanotherapeutic strategy for OA treatment. Download: Download high-res image (121KB) Download: Download full-size image