Nano Proton Scavengers Modulate Endosomal pH to Inhibit Microglial Activation and Enhance Stroke Recovery.

Endosomes play a crucial role in immune regulation, yet their effect on microglial behavior in ischemic stroke is not well-documented. While drug-loaded nanoparticles can modulate microglial inflammation, their intrinsic biological effects on microglial activation are underexplored. We demonstrate that inhibiting endosomal acidification reduces pro-inflammatory microglial polarization, limits pathological engulfment of neurons, and reduces neuronal apoptosis. To achieve the same effects in vivo, building on a validated dual-site buffering mechanism of sulfonated chitosan, we develop sulfonated Nano Proton Scavengers (sNPS) as a materials-based strategy to modulate endo/lysosomal pH. After cerebral ischemia, sNPS showed greater fluorescence-associated enrichment in the ipsilateral than in the contralateral hemisphere and was associated with brain-resident and infiltrating immune-cell populations. In the injured brain, sNPS alleviated endo/lysosomal acid stress, suppressed TLR3/4-linked inflammatory signaling, and normalized inflammation-driven endo/lysosomal remodeling and proton-loading machinery, thereby restraining maladaptive microglial activation. This immunomodulation was accompanied by improved neural structural preservation and post-stroke survival and functional outcomes. These findings identify endosomal pH homeostasis as a tractable intracellular cue for material-driven immunoregulation and suggest that sNPS offers a complementary therapeutic direction for ischemic stroke.