Multimodal nanoplatform for synergistic OA therapy via mitochondrial homeostasis restoration and photothermal intervention

• Neutralizes acidity & scavenges reactive oxygen species to break the inflammation-oxidative stress cycle. • By modulating the pathological microenvironment, this nano-platform restores mitochondrial homeostasis, thereby halting bone matrix loss and ultimately promoting bone regeneration. • Multimodal regulation and photothermal synergy therapy achieve rapid repair of osteoarthritis. Osteoarthritis (OA) is a progressive degenerative joint disorder that involves cartilage degeneration, chronic inflammation, and systemic complications. The pathological progression is exacerbated by an acidic microenvironment and reactive oxygen species (ROS)-induced oxidative stress, which collectively amplify inflammatory responses, and the degeneration of bone and cartilage matrix. Restoration of the joint cavity microenvironment balance has been identified as a critical therapeutic strategy for OA management. This study developed a novel Mg/Al layered double hydroxide-based nanoplatform (LDHs@P 1 S 5 ) incorporating platinum-doped selenium nanoclusters, which demonstrated multimodal microenvironmental regulation and photothermal capabilities for OA treatment. Upon intra-articular injection, the LDHs@P 1 S 5 nanoplatform first normalizes the acidic osteoarthritic microenvironment through its intrinsic pH-buffering capacity. Simultaneously, the loaded P 1 S 5 nanoparticles exhibit multi-enzyme-mimetic activity, effectively scavenging ROS to mitigate oxidative stress and restore mitochondrial functional homeostasis, thereby reducing degradation of bone and cartilage matrices. Furthermore, the LDHs@P 1 S 5 platform releases Mg 2+ that synergizes with P 1 S 5 to enhance M2 macrophage polarization while simultaneously activating osteoblast function, promoting bone tissue repair and regeneration. The versatile LDHs@P 1 S 5 platform also exhibits an excellent near-infrared-responsive photothermal effect, synergistically promoting bone regeneration through bone microenvironment remodeling and photothermal therapy, which holds great promise for the treatment of osteoarthritis.