Sinomenine hydrochloride-loaded liposomes-exosomes membrane fusion biohybrid attenuating collagen-induced rheumatoid arthritis via NF-κB pathway.

Sinomenine hydrochloride (SH) exhibits anti-inflammatory potential for rheumatoid arthritis (RA) but is hindered by suboptimal bioavailability. The NF-κB pathway, a central mediator of RA inflammation and immune dysfunction, remains a critical therapeutic target. Here, we engineered Sinomenine Hydrochloride-Loaded Liposomes-Exosomes Membrane Fusion Biohybrid (SHLE) to enhance SH delivery and achieve targeted NF-κB pathway modulation. Sinomenine hydrochloride-loaded liposomes (SHL) were prepared via thin-film dispersion and fused with exosomes using ultrasonic technology. In a collagen-induced arthritis (CIA) mouse model, therapeutic efficacy was evaluated through clinical scores, histopathological analysis, and serum biomarker profiling. NF-κB pathway activity was assessed via key regulatory proteins in joint tissues. SHLE demonstrated improved stability and cellular uptake in vitro compared to conventional liposomes. In CIA mice, SHLE treatment significantly alleviated arthritis symptoms, reduced joint inflammation, and restored immune organ indices. Serum levels of NF-κB-dependent inflammatory cytokines and RA-related immunoglobulins were markedly suppressed. Histopathological examination revealed preserved joint integrity with reduced synovial hyperplasia and cartilage erosion. Mechanistically, SHLE inhibited NF-κB pathway activation, as evidenced by increased IκBα expression and reduced nuclear translocation of phosphorylated p65. SHLE leverages exosome-liposome fusion technology to overcome SH's pharmacokinetic limitations, enabling targeted inhibition of the NF-κB pathway. This nanosystem effectively mitigates RA progression and joint damage in preclinical models, offering a promising platform for precision immunotherapy in autoimmune arthritis.