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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 \u03b1-syn\u2013specific recognition module with conformation-sensitive binding domains, and a protein regulatory module with a hydrophobic microdomain that can stabilize \u03b1-syn and prevent misfolding. Results demonstrate that CNMs can achieve active chemotactic navigation across BBB and dual modulation of \u03b1-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.<\/jats:p>","DOI":"10.1126\/sciadv.adw1061","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T17:58:44Z","timestamp":1758304724000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Chaperone nanomotors with chemotactic ability for the treatment of Parkinson\u2019s disease"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4812-9158","authenticated-orcid":true,"given":"Wenjing","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Technology, National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal 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