Nanoparticle-Driven Tendon Repair: Role of Vasoactive Intestinal Peptide in Immune Modulation and Stem Cell Enhancement

Tendon repair remains challenging owing to the limited capacity for endogenous repair. Vasoactive intestinal peptide (VIP) promotes bone tissue regeneration; however, its role in tendon repair remains unclear. In the present study, we demonstrated that VIP stimulated M2 polarization of macrophages and facilitated tendon regeneration by regulating immune homeostasis and maintaining the function of tendon stem/progenitor cells (TSPCs). Additionally, we established GelMa-loaded VIP@PLGA@ZIF-8 (VPZ) nanoparticles (VPZG) to enable the sustained and localized release of VIP at the site of patellar tendon injury in SD rats. The results of the <i>in vitro</i> experiments demonstrated that VPZG regulated the homeostasis of macrophage polarization by downregulating the NF-κB axis. VPZG also promoted efferocytosis and suppressed the release of proinflammatory factors. Additionally, VPZG enhanced the tenogenic differentiation of TSPCs when cocultured with macrophages. <i>In vivo</i>, we implanted VPZG at the site of patellar tendon injury, where it released VIP sustainably and slowly to promote tendon regeneration. This effect was achieved through the downregulation of the expression levels of various inflammatory factors, as well as the regulation of local immune homeostasis. In conclusion, our results demonstrated that VPZG facilitated tendon injury repair by regulating immune homeostasis and enhancing TSPC function. These findings suggest that VPZG is a promising avenue for the clinical improvement of tendon injury treatment.