Ion-GPS nanocapsules activate calcium-permeable gates in inflammatory microglia for nerve function recovery.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42699583.
- Also identified by DOI 10.1016/j.bioactmat.2026.08.041 and PMC identifier 13543907.
- Licence recorded as CC BY-NC-ND.
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Abstract
Microglia (MG)-mediated immune responses play a pivotal role in the pathophysiological progression and prognosis of spinal cord injury (SCI). However, systematic investigations into the reprogramming of calcium (Ca<sup>2+</sup>) crosstalk at the subcellular organelle level to modulate MG inflammatory phenotypes remain limited. In this study, we introduced the novel concept of "Ca<sup>2+</sup> storage reprogramming," which refers to replenishing endoplasmic reticulum (ER) Ca<sup>2+</sup> reserves and re-establishing ER-mitochondrial Ca<sup>2+</sup> crosstalk, rather than simply reducing cytoplasmic Ca<sup>2+</sup> (CytCa<sup>2+</sup>) overload as in conventional chelation-based strategies. Using an optimized method combining differential centrifugation with preconcentration and size exclusion chromatography, we successfully purified <i>Salvia miltiorrhiza Bge.</i>-derived nanovesicles (SDNVs). SDNVs restored ER homeostasis and ER-mitochondrial Ca<sup>2+</sup> coupling by modulating the Snail1/STIM1/SOCE/STING signaling axis, consequently systematically suppressing the cGAS-STING-NFκB-mediated inflammatory pathway. To further enhance therapeutic precision, we designed an ion-GPS nanocapsule system (SDNVs-MG1) by conjugating SDNVs with an MG1-targeting peptide. This construct integrated precise M1-type MG navigation with the inherent regulatory bioactivity of plant-derived vesicles, facilitating neural regeneration following SCI. <i>In vitro</i>, SDNVs-MG1 achieved 84.8% targeting efficiency by flow cytometry within 24 h and enhanced neural repair and regeneration by 22.4% compared with unmodified SDNVs by immunofluorescence staining and Western blot. <i>In vivo</i>, SDNVs-MG1 regulated MG-mediated inflammation in the early post-injury phase, thus promoting neural functional recovery. These findings provide a foundation for applying bioengineered plant exosome-inspired strategies in SCI repair and offer valuable insights for developing advanced therapeutic materials in regenerative medicine.