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.