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In this study, we developed a versatile targeted celastrol nanoassembly (CDPG) that integrates site\u2010specific antibacterial delivery with coordinated immunomodulation to effectively address MRSA infections and prevent their recurrence. The nanoassembly consists of a celastrol\u2013dextran antibacterial core encapsulated by a polyethylene glycol (PEG) shell, which is linked via pH\u2010sensitive boronate ester bonds and stabilized through the reconstitution of the \u03b2\u2010glucan triple\u2010helix structure. This design enables prolonged systemic circulation under physiological conditions. Upon reaching the acidic microenvironment of the bacterial infection site, the nanoassembly undergoes PEG layer dissociation, exposing dextran moieties that enhance pathogen targeting through lectin\u2010mediated recognition, while simultaneously releasing \u03b2\u2010glucan to activate both innate and adaptive immune responses. In murine models of MRSA infection, CDPG demonstrated precise accumulation at lesion sites, potent bactericidal efficacy, modulation of inflammatory responses, and induction of systemic immune activation upon rechallenge. This study presents a natural product\u2010derived, rationally designed nanomedicine strategy that integrates stimulus\u2010responsive structural transformation, pathogen\u2010targeted drug delivery, and modulation of the host immune system, offering a hopeful therapeutic approach to combat multidrug\u2010resistant bacterial infections.\n                  <\/jats:p>","DOI":"10.1002\/smll.74467","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:32:13Z","timestamp":1783513933000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Versatile Targeted Celastrol Nanoassemblies for Enhanced Immunomodulatory Effects Against MRSA Infection"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0208-3834","authenticated-orcid":false,"given":"Yadan","family":"Zheng","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Northeast 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