Dual-engineered Treg-Exosome-IKVAV nanovesicles spatiotemporally sequentially regulate neuro-immune microenvironment to promote spinal cord injury repair

Spinal cord injury (SCI) repair remains a significant clinical challenge due to the imbalance of inflammatory microenvironment and insufficient neural regenerative ability. Current therapeutic approaches, such as pharmaceuticals, stem cell transplantation, and inorganic biomaterials, are limited by insufficient supply, poor bioactivity, and immunogenicity, severely limiting their clinical translation. To address these issues, we developed a biomimetic dual-engineered nanovesicles (Treg-Exo-IKVAV) by conjugating a neuroprotective IKVAV peptide motif with Treg-derived exosomes (Treg-Exo) using click chemistry. This system synergistically integrates the intrinsic immunomodulatory properties of Treg-Exo (early-stage anti-inflammation) with the neural regenerative capability of IKVAV, enabling spatiotemporally sequential regulation of neuro-regeneration. In vitro studies demonstrated that Treg-Exo-IKVAV suppressed macrophage-induced inflammatory responses by reprogramming macrophage polarization. Furthermore, Treg-Exo-IKVAV exerts dual direct and immunoregulatory effects on promoting neuronal differentiation of stem cells (NSCs). In vivo experiments revealed that Treg-Exo-IKVAV via tail vein injection precisely targeted and accumulated at the injured site. Subsequently, the functional assessments showed that Treg-Exo-IKVAV significantly enhanced motor functional recovery in SCI mice. Mechanistically, these nanovesicles reshaped the neuro-immune microenvironment through a two-phase mechanism: initial suppression of inflammation via Treg-derived anti-inflammatory signaling followed by activation of neuro-regenerative pathways mediated by IKVAV. This integrated “exosome-peptide” nanocomposite combining immunomodulation and neuronal regeneration provides a highly efficient and safe therapeutic solution for SCI. SCI repair remains a challenge due to the neuro-immune dysfunction and limited neuro-regeneration capability. Treg-Exo-IKVAV nanovesicles showed immunomodulatory property, regulating macrophage phenotype transition toward M2 phenotype. Treg-Exo-IKVAV nanovesicles showed potent dual effects in both direct NSCs differentiation and immune-mediated NSCs differentiation in vitro. Treg-Exo-IKVAV nanovesicles spatiotemporally and sequentially regulated neuro-immune microenvironment to promote SCI repair in vivo.