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

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

Xuanlin Wang 1,2, Yujing Shi 1,2, Zehua Gao 1,2, Jing Wang 1,2,✉, Changsheng Liu 2,3,✉

PMCID: PMC13496290  PMID: 42627642

ABSTRACT

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.

Keywords: endosomes, inflammation, ischemic stroke, microglia, toll‐like receptors

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Amphiphilic sulfonated chitosan nanoparticles buffer endo/lysosomal acidity in microglia by limiting V‐ATPase membrane recruitment and restoring endosomal homeostasis. Following systemic administration, they accumulate in the ischemic hemisphere partly through association with infiltrating immune cells, suppress TLR3/IRF3 and TLR4/NF‐κB signaling, reshape the inflammatory microenvironment, and promote neural repair and functional recovery after stroke.

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