Engineered nano-lubricant with photothermal-triggered drug release and acid-degradable ion delivery for osteoarthritic microenvironment regulation

The progression of osteoarthritis (OA) is driven by a complex interplay of pathological mechanisms, including oxidative stress imbalance, inflammatory cascade amplification, and irreversible cartilage degradation, which pose significant challenges for effective therapeutic intervention. Conventional single-stimulus responsive drug delivery systems often exhibit insufficient sensitivity under complex pathological conditions, whereas multi-modal stimulation strategies significantly enhance the precision and controllability of drug release. In this study, a photothermally-triggered multimodal controlled-release nano-system (MoS 2 -LS@QZTL) was innovatively developed to address these challenges. At the initial stage of treatment, the exposure of leonurine (Leo) was triggered via photothermal effects, followed by reactive oxygen species (ROS) scavenging and polarization of synovial macrophages toward the M2 phenotype. This process modulated the inflammatory microenvironment in osteoarthritis, thereby creating an optimal immune environment for cartilage repair. In the second stage, the damaged cartilage is specifically targeted via negative charge recognition, with subsequent acid-triggered degradation enabling controlled release of Zn 2+ and Ca 2+ to orchestrate osteochondral microenvironment remodeling and tissue regeneration. Furthermore, the nanocomposite platform exhibits excellent lubrication performance, effectively minimizing interosseous friction to prevent progressive inflammatory deterioration and osteoclasia. This study establishes a pioneering approach by orchestrating multidimensional physicochemical and biological regulatory mechanisms to achieve spatiotemporal synchronization between inflammatory microenvironment modulation and cartilage regeneration.