Photothermal‐Driven Spatiotemporal Delivery of Bioactive Facilitators for Coordinated Cartilage and Subchondral Bone Regeneration in Osteoarthritis

Abstract Osteoarthritis (OA) is a complex degenerative disorder involving cartilage erosion, subchondral bone remodeling, and persistent inflammation, with no effective disease‐modifying treatments available. Conventional single‐target strategies achieve limited outcomes, highlighting the need for approaches that restore overall joint homeostasis. Here, a multifunctional nanozyme (CPMP, CeO 2 @PDA‐Mg@PTHrP‐2) is designed, fabricated by coating CeO 2 with Mg 2 ⁺‐doped polydopamine and immobilizing parathyroid hormone‐related peptide 2 (PTHrP‐2). The CPMP nanozyme exhibits potent antioxidase‐mimicking activity, scavenging over 80% of ROS/RNS (H 2 O 2 , •OH, •O 2− , DPPH, ABTS⁺) while simultaneously generating O 2 . Upon near‐infrared (NIR) irradiation, CPMP demonstrates efficient photothermal conversion, enabling controlled Mg 2 ⁺ and PTHrP‐2 release while inducing HSP70 expression, thereby promoting chondrocyte proliferation, matrix preservation, and oxidative stress resistance. Mechanistically, CPMP‐NIR activation enhances chondrocyte proliferation and chondrogenesis by suppressing JAK/STAT3 signaling and activating the PI3K/AKT pathway. It also drives M1‐to‐M2 macrophage polarization, modulates the osteoimmune microenvironment, recruits mesenchymal stem cells, enhances osteogenesis, and inhibits osteoclastogenesis. In a rat OA model, CPMP‐NIR effectively alleviated inflammation, reduced bone resorption, prevented periarticular bone remodeling, and protected cartilage integrity. This spatiotemporally controlled system integrates antioxidative, immunomodulatory, and regenerative functions, offering a synergistic therapy for cartilage and subchondral bone. The CPMP nanozymes represent a promising, potentially transformative strategy for OA and related inflammatory diseases.