Controlled Activation of TRPV1 Channels on Microglia to Boost Their Autophagy for Clearance of Alpha‐Synuclein and Enhance Therapy of Parkinson's Disease

Parkinson's disease (PD) is characterized with accumulation of Lewy bodies with a major component of fibrillar alpha-synuclein (α-syn). Herein, boosting PD therapeutic efficacy by enhancing the autophagy of microglia to phagocytose and degrade α-syn via controlled opening of their surface TRPV1 channels with rationally designed photothermal nanoagent is reported. The Cu2-x Se-anti-TRPV1 nanoparticles (CS-AT NPs) are fabricated 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 promote phagocytosis and degradation of α-syn. The CS-AT NPs are efficiently delivered by focused ultrasound into striatum of PD mice with high expression of TRPV1 receptors. The athletic ability of PD mice treated by CS-AT NPs and NIR-II irradiation is 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 are almost recovered to the normal levels of healthy mice. This study provides insights into the activation of microglial autophagy by targeting surface ion channels to improve the treatment of PD and other neurodegenerative diseases.