Ion-GPS nanocapsules activate calcium-permeable gates in inflammatory microglia for nerve function recovery

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 (Ca²⁺) crosstalk at the subcellular organelle level to modulate MG inflammatory phenotypes remain limited. In this study, we introduced the novel concept of "Ca²⁺ storage reprogramming," which refers to replenishing endoplasmic reticulum (ER) Ca²⁺ reserves and re-establishing ER-mitochondrial Ca²⁺ crosstalk, rather than simply reducing cytoplasmic Ca²⁺ (CytCa²⁺) overload as in conventional chelation-based strategies. Using an optimized method combining differential centrifugation with preconcentration and size exclusion chromatography, we successfully purified Salvia miltiorrhiza Bge.-derived nanovesicles (SDNVs). SDNVs restored ER homeostasis and ER-mitochondrial Ca²⁺ 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. In vitro, 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. In vivo, 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.