A Photothermal Transducer Regulates Transmembrane Calcium Flow for Synergistic Osteoarthritis Therapy

ABSTRACT 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.