...Herein, we report the clearance of α-syn to boost PD therapeutic efficacy by enhancing the autophagy of microglia via controlled opening of their surface TRPV1 channels with rationally designed photothermal nanoagent. We prepared Cu2- x Se-anti-TRPV1 nanoparticles (CS-AT NPs) to target the microglia and open their surface TRPV1 channels under the second near infrared (NIR-II) laser irradiation to cause influx of Ca2+ to activate ATG5 and Ca2+ /CaMKK2/AMPK/mTOR signaling pathway, which promoted phagocytosis and degradation of α-syn. By using focused ultrasound, we efficiently delivered CS-AT NPs into striatum of PD mice with high expression of TRPV1 receptors. We demonstrate that the athletic ability of PD mice treated by CS-AT NPs and NIR-II irradiation was significantly improved due to the phagocytotic clearance of α-syn by microglia with enhanced autophagy. The enzyme tyrosine hydroxylase, ionized calcium binding adapter protein 1, glial fibrillary acidic protein and pSer129-α-syn (p-α-syn) of treated PD mice were almost recovered to the normal levels of healthy mice...