Chemically Programmed Prodrug Nanoparticles for Precise Oral Dopamine Delivery to Deep Brain Regions in Parkinson's Disease

ABSTRACT Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the inflamed substantia nigra, resulting in striatal dopamine (DA) depletion and severe motor dysfunction. Here, we report a chemically programmed, inflammation‐responsive prodrug nanoparticle (NP) system—β‐glucans–DA(OAc) 2 NPs—that enables precise oral gut‐to‐brain delivery of DA into deep brain regions. In this design, the acetylated DA prodrug DA(OAc) 2 is conjugated to β‐glucans via a reactive oxygen species (ROS)–cleavable thioketal linker, thereby preventing DA autooxidation, enhancing stability during transit, and ensuring selective activation at neuroinflammatory sites. Following oral administration in PD mice, the NPs are recognized by Dectin‐1, internalized by intestinal macrophages, and trafficked through the lymphatic and systemic circulation to cross the blood–brain barrier, ultimately homing specifically to the inflamed substantia nigra in the deep brain. Within this pathological niche, dual responsiveness to elevated ROS and enzymatic activity triggers controlled prodrug cleavage, sustained DA regeneration, and restoration of striatal DA via the nigrostriatal pathway, ultimately rescuing motor function. This inflammation‐guided, modular prodrug platform provides a noninvasive and precise strategy for dopaminergic therapy, underscoring its potential as a transformative approach for PD management.