PLL‐g‐HPA Hydrogel Microneedles Loaded With Rhoifolin Target Macrophages to Alleviate Fibroblast Senescence for Diabetic Wound Healing

Abstract

In this study, we demonstrate that during diabetic wound healing, interleukin-11 (IL-11) promotes the M1 polarization of macrophages, which subsequently triggers fibroblast senescence through the enhanced release of pro-inflammatory cytokines IL-1β and IL-6. Notably, Rhoifolin (Rho) effectively inhibits IL-11-induced M1 polarization, alleviates the secretion of IL-1β and IL-6, and concurrently promotes the release of choline, thereby mitigating fibroblast senescence. Based on these mechanistic findings, we constructed a targeted delivery system by loading Rho into mesoporous silica nanoparticles and coating them with macrophage membranes (M-Rho). The M-Rho were then incorporated into a poly(L-lysine)-grafted hyperbranched poly(amidoamine) (PLL-g-HPA) hydrogel to fabricate microneedles (Gel@M-Rho MN). This integrated system enables macrophage targeting, controlled drug release, favorable mechanical properties, and excellent biocompatibility. Moreover, the system exhibits potent reactive oxygen species (ROS)-scavenging activity and effectively inhibits the growth of Escherichia coli and Staphylococcus aureus. In vivo animal studies confirmed that Gel@M-Rho MN significantly promotes M2 macrophage polarization, suppresses fibroblast senescence, and accelerates wound closure, angiogenesis, and collagen deposition. Collectively, this strategy, which modulates macrophage-fibroblast crosstalk, offers a multi-mechanistic synergistic therapeutic approach for diabetic wounds, holding substantial potential for clinical translation.