A Photothermal Transducer Regulates Transmembrane Calcium Flow for Synergistic Osteoarthritis Therapy.

Hyperthermia is a well-established physical therapy modality used in orthopedics as an alternative treatment for osteoarthritis (OA). However, the precise cellular-level interventions and intrinsic mechanisms regulating the joint microenvironment remain poorly understood. In this study, we developed a near-infrared (NIR)-responsive nanotransducer composed of selenium-doped carbon quantum dots attached to black phosphorus nanosheets and coated with a membrane derived from M2 macrophages (M2M), termed M2M@BPSC. Upon NIR stimulation, M2M@BPSC selectively induced mild hyperthermia in macrophages, thereby inhibiting the transient receptor potential vanilloid type 4 (TRPV4) channel to inhibit calcium ion influx and prevent calcium overload-induced mitochondrial dysfunction. Furthermore, TRPV4 suppression promotes the nuclear translocation of signal transducer and activator of transcription 6 dimers, enhancing the transcriptional activity of early growth response 2. This activates the expression of M2-polarization-associated genes. Programmed M2M exerts bidirectional regulatory effects on both chondrocytes and fibroblast-like synoviocytes, thereby restoring the balance between cartilage extracellular matrix (C-ECM) degradation and fibrosis ECM (F-ECM) production. Overall, we identified a thermosensitive ion channel-targeting strategy that effectively modulates the pathological microenvironment in OA.