An Implant-Free Nanosystem Enabling Synergistic Oxidative Damage Mitigation and Deep Brain Stimulation for Alleviating Parkinsonian Symptoms

Deep brain stimulation (DBS) effectively alleviates motor symptoms in Parkinson's disease (PD) patients; however, it necessitates permanent invasive implantation of conduits, and its therapeutic effects diminish as PD progresses. Herein, an implant-free NIR-II laser-activated intervention nanosystem that combines wireless DBS with antioxidative neuroprotection is developed to overcome the above challenges. Enzyme-like 2-(phenylselanyl)ethan-1-amine (SePh) and manganese dioxide (MnO₂) and NIR-II absorber IR-1048 (IR) are integrated onto the mesoporous polydopamine (mPDA) core to form mPDA-SeMn-IR. Upon NIR-II laser irradiation, intraventricularly injected mPDA-SeMn-IR nanoparticles effectively activate endogenously expressed inositol 1,4,5-trisphosphate receptors, leading to Ca²⁺ outflux from the endoplasmic reticulum. Ca²⁺ signaling enhances tyrosine hydroxylase expression and activity and triggers dopamine release to enhance dopaminergic function. Meanwhile, mPDA-SeMn-IR rapidly eliminates excessive reactive oxygen species, synergistically enhancing long-term DBS efficiency by increasing neuron survival and restoring neuronal function for improved dopamine secretion. <i>In vivo</i>, mPDA-SeMn-IR regulates midbrain neurons and coiling behaviors in zebrafish and considerably alleviates motor symptoms in the PD model, proposing a promising therapeutic strategy to address existing challenges in PD therapies.