Localised delivery of interleukin-13 from a PLGA microparticle embedded GelMA hydrogel improves functional and histopathological recovery in a mouse contusion spinal cord injury model

Spinal cord injury (SCI) is a severe neurological condition with limited regenerative capacity and no effective curative treatments. Interleukin-13 (IL-13), an immunomodulatory cytokine, has shown therapeutic potential by promoting alternative immune activation and improving recovery after SCI in mice. However, cell-based IL-13 delivery is hindered by poor graft survival and limited localisation at the injury site. Here, we developed an injectable hydrogel-based delivery system (HGIL13) composed of IL-13-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles embedded in a photocrosslinkable gelatin methacrylate (GelMA) matrix, enabling sustained and localised IL-13 release. HGIL13 achieved IL-13 release for up to six weeks and significantly reduced lipopolysaccharide (LPS)-induced inflammation in BV2 microglia <i>in vitro</i>. In a mouse contusion SCI model, HGIL13 enhanced functional recovery, reduced lesion volume, and decreased demyelinated area. Using the Hexb^tdTomato mouse we show that HGIL13 modulated the neuroimmune response by decreasing resident microglia density, downregulating CD86 expression, and upregulating Arginase-1 in both microglia and infiltrating monocyte-derived macrophages. RT-qPCR and RNA-seq analyses confirmed sustained immunomodulation over 28 days and indicated early reduction of activated microglia at 7 days post-injury as a key therapeutic mechanism. This study presents a safe, effective, and translatable strategy for localised cytokine delivery, demonstrating strong potential for immunomodulation and improved functional recovery following SCI.