Enhancing Exosomes Efficacy with Engineered Nanozymes for a Multi-Targeted Combination Strategy in Osteoarthritis Treatment

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by multifactorial pathological mechanisms, and remains a significant clinical challenge. Exosome therapy represents a future direction for delaying OA progression, yet its efficacy is often compromised by inflammatory microenvironment within the joints. To overcome these limitations, we present a novel combinatorial therapeutic platform that alleviates OA through a multi-targeted strategy, including the scavenging of reactive oxygen species (ROS), suppression of macrophage-driven inflammation, and inhibition of chondrocyte ferroptosis. This platform combines dental pulp stem cells-derived exosomes (Exo) with hollow mesoporous cerium oxide nanozymes, which were first loaded with curcumin and subsequently coated with hyaluronic acid, termed HA@Cur@CeO 2 . In vitro , this combination reduced intracellular ROS and promoted macrophage polarization toward the anti-inflammatory M2 phenotype, thereby remodeling the OA microenvironment and halting the inflammatory cascade. Additionally, Exo and HA@Cur@CeO 2 nanozymes complementarily modulated ALOX12- and GPX4-dependant ferroptosis pathways in chondrocytes, with the combined approach yielding superior anti-ferroptotic effects. For in vivo assessment, Exo and HA@Cur@CeO 2 were encapsulated within a chitosan/β-glycerophosphate hydrogel to achieve sustained release (Exo/HA@Cur@CeO 2 /Gel). This formulation significantly reduced inflammation, chondrocyte ferroptosis, cartilage degeneration, and subchondral bone remodeling, ultimately slowing OA progression. With excellent biocompatibility, this innovative combinatorial therapeutic strategy represents a comprehensive approach for enhancing Exo efficacy in OA treatment with promising translational potential.