Chaperone nanomotors with chemotactic ability for the treatment of Parkinson's disease.

Abstract

Aggregation of α-synuclein (α-syn) represents a pathogenic hallmark of Parkinson's disease (PD). Using exogenous molecular chaperone systems has the potential to stabilize native conformations and inhibit the aberrant aggregation of α-syn, yet inefficient blood-brain barrier (BBB) penetration and insufficient accumulation at PD sites limit their application. Herein, we developed chemotactic chaperone nanomotors (CNMs) that exploit the unique pathological microenvironment of PD lesions, characterized by elevated inducible nitric oxide synthase (iNOS) levels. The CNMs consist of a chemotactic-targeting module capable of sensing an iNOS concentration gradient, an α-syn-specific recognition module with conformation-sensitive binding domains, and a protein regulatory module with a hydrophobic microdomain that can stabilize α-syn and prevent misfolding. Results demonstrate that CNMs can achieve active chemotactic navigation across BBB and dual modulation of α-syn proteostasis through aggregate dissolution and prevention of misfolding. CNMs not only supplement exogenous chaperone activity but also restore endogenous protein stabilization mechanisms, concurrently reducing neuroinflammatory markers, promoting the application of nanochaperones for PD treatment.