Bioresponsive PDA-GelMA hydrogel microspheres coordinate redox-immune homeostasis via controlled rhMUC13 delivery for radiation-induced intestinal injury

Radiation-induced intestinal injury (RIII) remains a major clinical challenge, partly due to the lack of local delivery systems capable of concurrently coordinating oxidative stress and immune responses at the lesion site. In this study, we identify the transmembrane mucin MUC13 as a key regulator of intestinal epithelial homeostasis. MUC13 deficiency aggravates oxidative stress, epithelial apoptosis, and inflammatory responses, whereas supplementation with recombinant human MUC13 (rhMUC13) markedly attenuates epithelial injury. To achieve site-specific and durable delivery to inflamed tissue, we developed an inflammation-responsive polydopamine-gelatin methacryloyl (PDA-GelMA) hydrogel microsphere system that integrates targeted local delivery with intrinsic microenvironment modulation. The therapeutic efficacy arises from complementary, component-specific functions. The PDA shell mediates inflammation-associated adhesion and prolonged mucosal retention, rapidly scavenges reactive oxygen species (ROS), suppresses early inflammatory amplification, and promotes macrophage polarization toward a reparative M2 phenotype. Within this favorable redox-immune milieu, the GelMA core enables sustained rhMUC13 release, enhancing epithelial survival and barrier reconstruction by inhibiting NF-κB-associated pro-apoptotic signaling (the Bax/Bcl-2 axis) and restoring tight-junction proteins (ZO-1, Occludin, and Claudin-1). This cooperative mechanism likely accounts for the superior efficacy of the composite microspheres compared with single-component controls. Moreover, 16S rRNA gene sequencing revealed that irradiation induces pronounced gut microbiota dysbiosis, characterized by disrupted microbial diversity and community structure, increased inflammation-associated opportunistic taxa, and reduced beneficial commensal/metabolism-related bacteria; notably, PDA-GelMA@rhMUC13 partially ameliorated irradiation-induced dysbiosis, showing an overall remodeling trend toward reduced inflammation-associated taxa and increased putatively beneficial and metabolism-related bacteria. Collectively, these findings establish MUC13 as a critical mediator of epithelial-immune crosstalk and introduce a multifunctional hydrogel microsphere platform that combines targeted protein delivery with endogenous antioxidative and immunomodulatory capacities. This strategy may additionally promote restoration of intestinal homeostasis through microbiota remodeling, offering translational potential for RIII and other inflammatory intestinal disorders.