Biomimetic priming of hMSC aggregates with cadherin-IL-1β synergistic microparticles enhances immune homeostasis in inflammatory bowel disease

Inflammatory bowel disease (IBD) is an incurable condition driven by chronic inflammatory dysregulation. Human mesenchymal stem cells (hMSCs) offer therapeutic promise, but limited persistence and functional heterogeneity constrain their clinical efficacy. Here, we present a bio-inspired priming platform built on poly(lactic- co -glycolic acid)/chitosan-heparin microparticles, engineered to display E/N-cadherin motifs and to enable controlled interleukin-1β release through PLGA biodegradation. These functionalized microparticles (hE/N-cad@P/C-h-IL-1β) assemble with hMSCs into hybrid aggregates that enhance cell survival under stress and improve adaptability to microenvironment cues. The priming process upregulates endogenous cadherin expression and modulates AKT/STAT signaling, conferring stimulus- and dose-responsive immune activity. In vitro , hybrid aggregates polarize macrophages toward an anti-inflammatory phenotype, expand regulatory T cells, and suppress pathogenic lymphocyte activation. In a dextran sulfate sodium (DSS) colitis model, intraperitoneal delivery of hybrid aggregates restores intestinal immune homeostasis, accelerates epithelial repair, and reduces disease severity to near baseline within fourteen days. By integrating cell-adhesive and cytokine signals within a modular platform, this strategy overcomes critical translational barriers in hMSC therapy and provides a blueprint for precisely targeted treatment of IBD and related inflammatory disorders.