Self-assembled nanoparticles from natural herbs alleviate osteoarthritis by targeting retinol metabolism and inhibiting chondrocyte ferroptosis

Osteoarthritis (OA), a prevalent degenerative joint disease, currently lacks effective therapies. Self-assembled nanomedicines derived from herbs create innovative pharmaceutical formulations, and offer promising therapeutic strategies for OA treatment. Considering the treatment of Shen-Sui-An-Kang (SSAK) decoction in clinical OA symptoms, here we isolated the nanoparticles from SSAK decoction, and then investigated their effects on OA treatment. By using gradient centrifugation and dialysis, self-assembled nanoparticles of SSAK (N-SSAK) were isolated based on the hydrophobic interactions, hydrogen bonding, and π-π stacking. After determining the physical characteristics of N-SSAK, we investigated the therapeutic effect of N-SSAK in vivo and in vitro , and found that they alleviated cartilage degeneration, maintained the homeostasis of cartilage matrix, and reduced pain sensitivity. Mechanistically, we demonstrated that N-SSAK exerted their effects by modulating retinol metabolism and inhibiting lipid peroxidation in OA chondrocytes. To improve the sustained release and targeted delivery of N-SSAK, we developed an injectable hydrogel-based delivery system (HA-MIX@N-SSAK). Compared to N-SSAK oral administration, HA-MIX@N-SSAK showed better efficacy on cartilage protection and slowing OA progression. Overall, our findings indicate that N-SSAK suppress the progression of OA by regulating retinol metabolism and inhibiting chondrocyte ferroptosis, implying that HA-MIX@N-SSAK may be a novel strategy for clinical OA treatment.