Controlled Release of Ceria and Ferric Oxide Nanoparticles via Collagen Hydrogel for Enhanced Osteoarthritis Therapy

Abstract Osteoarthritis (OA), characterized by chronic inflammation and cartilage degeneration, significantly affects over 500 million people globally. Nanoparticles have emerged as promising treatments for OA; however, current strategies often employ a single type of nanoparticle targeting specific disease stages, limiting sustained therapeutic efficacy. In this study, a novel collagen hydrogel is introduced, thiol crosslinked collagen‐cerium oxide‐poly(D,L‐lactic‐co‐glycolic acid) microspheres encapsulating nanoparticles (CSH‐CeO 2 ‐pFe 2 O 3 ), designed for the controlled release of cerium oxide (CeO 2 ) and ferric oxide (Fe 2 O 3 ) nanoparticles for comprehensive OA management. The sulfhydryl cross‐linked collagen matrix embeds CeO 2 nanoparticles and poly(D,L‐lactic‐co‐glycolic acid) (PLGA) microspheres encapsulating Fe 2 O 3 nanoparticles. The CSH‐CeO 2 ‐pFe 2 O 3 hydrogel exhibits enhanced mechanical strength and remarkable injectability, along with a significant promotion of cell adhesion, proliferation, and chondrogenic differentiation. Notably, the hydrogel demonstrates intelligent responsiveness to high levels of reactive oxygen species, initiating the rapid release of CeO 2 nanoparticles to address the intense inflammatory responses of early‐stage OA, followed by the sustained release of Fe 2 O 3 nanoparticles to facilitate cartilage regeneration during the proliferative phase. In a rat model with cartilage defects, the hydrogel significantly alleviates inflammation and enhances cartilage regeneration, holding substantial potential for effectively managing the pathologically complex OA.