Wireless Electrical Stimulation via Piezoelectric Nanogenerator for Parkinson's Disease Therapy Through Activating Calcium Channels and Mitigating Oxidative Damage

ABSTRACT The primary pathological hallmarks of Parkinson's disease (PD) comprise the loss of dopaminergic neurons in the substantia nigra and abnormal accumulation of α‐synuclein, accompanied by severe oxidative damage due to excessive reactive oxygen species (ROS). Clinical electrical stimulation therapies pose invasive risks from long‐term electrode implantation with neuroinflammation side effects, while antioxidant drugs for scavenging brain ROS also fail to meet clinical demands due to poor blood–brain barrier permeability and short half‐lives. Herein, we report a brain‐targeted piezoelectric nanogenerator (PEL) for wireless electrotherapy for PD. Under ultrasonic stimulation, the piezoelectrically induced output current generated by the PEL promotes voltage‐gated calcium channel‐mediated calcium influx, upregulating tyrosine hydroxylase expression to promote dopamine synthesis. Concurrently, acting as a piezoelectric catalyst, the PEL rapidly decomposes water to continuously release hydrogen, which scavenges excess ROS and mitigates oxidative damage. In the mouse model of PD, the ultrasound‐responsive PEL nanogenerator alleviated the symptoms of the disease without causing obvious toxicity. This synergistic approach targeting ion channels and hydrogen therapy may inspire the development of other minimally invasive therapeutic strategies for PD.