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While drug\u2010loaded nanoparticles can modulate microglial inflammation, their intrinsic biological effects on microglial activation are underexplored. We demonstrate that inhibiting endosomal acidification reduces pro\u2010inflammatory microglial polarization, limits pathological engulfment of neurons, and reduces neuronal apoptosis. To achieve the same effects in vivo, building on a validated dual\u2010site buffering mechanism of sulfonated chitosan, we develop sulfonated Nano Proton Scavengers (sNPS) as a materials\u2010based strategy to modulate endo\/lysosomal pH. After cerebral ischemia, sNPS showed greater fluorescence\u2010associated enrichment in the ipsilateral than in the contralateral hemisphere and was associated with brain\u2010resident and infiltrating immune\u2010cell populations. In the injured brain, sNPS alleviated endo\/lysosomal acid stress, suppressed TLR3\/4\u2010linked inflammatory signaling, and normalized inflammation\u2010driven endo\/lysosomal remodeling and proton\u2010loading machinery, thereby restraining maladaptive microglial activation. This immunomodulation was accompanied by improved neural structural preservation and post\u2010stroke survival and functional outcomes. These findings identify endosomal pH homeostasis as a tractable intracellular cue for material\u2010driven immunoregulation and suggest that sNPS offers a complementary therapeutic direction for ischemic stroke.<\/jats:p>","DOI":"10.1002\/advs.77311","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:29:35Z","timestamp":1787322575000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nano Proton Scavengers Modulate Endosomal pH to Inhibit Microglial Activation and Enhance Stroke Recovery"],"prefix":"10.1002","author":[{"given":"Xuanlin","family":"Wang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai P. R. 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