Carnosine-modified gelatin-hyaluronic acid hydrogel comprising fenofibrate-loaded nanoparticles targeting chondrocyte ferroptosis and macrophage polarization for synergistic osteoarthritis therapy.

Osteoarthritis (OA), a debilitating and progressive joint disease, presents major therapeutic challenges due to chondrocyte ferroptosis, chronic synovial inflammation, and the pharmacokinetic limitations of conventional intra-articular therapies, such as rapid clearance and poor retention. To overcome these barriers, we developed a dual-functional intra-articular delivery platform composed of a gelatin-hyaluronic acid hydrogel encapsulating fenofibrate-loaded, cartilage-targeting nanoparticles (FNPs-GelHA hydrogel). This system synergistically inhibits OA progression by simultaneously suppressing chondrocyte ferroptosis and modulating the inflammatory joint microenvironment. In vitro studies revealed that FNPs-GelHA hydrogel markedly attenuates chondrocyte ferroptosis, inflammation, oxidative stress, and lipid peroxidation. Furthermore, this system effectively reprograms macrophage polarization by suppressing pro-inflammatory M1 phenotypes and promoting reparative M2 phenotypes, thereby contributing to immunomodulation and cartilage repair. In addition, in vivo experiments demonstrated prolonged joint retention of this system and significant therapeutic efficacy in delaying OA progression. By integrating targeted drug delivery, ferroptosis inhibition, and immune microenvironment remodeling, this composite hydrogel-nanoparticle platform offers a synergistic and promising strategy for OA treatment.