Application of hybrid exosomes-mediated targeted delivery system for sinomenine hydrochloride in rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction, whose pathogenesis is closely associated with dysregulated macrophage polarization. Recent evidence highlights the inherent anti-inflammatory properties of exosomes derived from M2-macrophages (M2-Exo), positioning them as promising bioinspired vehicles for targeted delivery to inflammatory sites. Here, we present an innovative hybrid exosome system (SH@M2-Exo-Lip) for targeted RA therapy. This system was constructed via the fusion of sinomenine hydrochloride (SH)-loaded liposomes with M2-Exo, specifically designed to improve the drug loading capacity of exosomes and enhance the targeting efficacy of drug delivery systems. The results demonstrated that leveraging the innate targeting capability of M2-Exo, the SH@M2-Exo-Lip system achieved selective accumulation within inflamed joints in the collagen-induced arthritis model, enabling precise SH release at pathological sites, and significantly reduced levels of pro-inflammatory cytokines and ameliorated arthritic symptoms. Furthermore, SH@M2-Exo-Lip efficiently scavenged the excess reactive oxygen species and modulated the critical cGAS-STING innate immune pathway, thereby synergistically promoting the polarization of M1 macrophages towards the M2 phenotype, effectively ameliorating the joint microenvironment. Consequently, our study presents an innovative engineered hybrid exosome platform that offers a novel therapeutic strategy for RA treatment.