Smart glucose-ROS responsive CPOD/MGF@GMs hydrogel for mangiferin-mediated diabetic wound healing

Mangiferin (MGF), a natural glucosylxanthone with pro-angiogenic, anti-inflammatory, antioxidant, and anti-diabetic properties, is a promising candidate for diabetic wound healing. However, its topical application remains underexplored due to delivery limitations. Herein, we developed a smart dual-responsive chitosan/alginate hydrogel (CPOD) encapsulating MGF-loaded gelatin microspheres (MGF@GMs) for glucose- and reactive oxygen species (ROS)-triggered drug release. The CPOD/MGF@GMs hydrogel exhibited excellent self-healing capability (95% strain recovery), tissue adhesiveness (23.12 ± 6.58 kPa), and on-demand MGF release under pathological microenvironmental conditions (high glucose/ROS). In vitro assays confirmed its biocompatibility and potent pro-angiogenic effects (4–6-fold upregulation of CD31, FGF, and VEGF mRNA in HUVECs). In a diabetic full-thickness skin injury model, the hydrogel significantly accelerated wound closure (92.57% ± 2.60% healing rate within 14 days), enhanced re-epithelialization, promoted collagen deposition, and suppressed pro-inflammatory markers (84.21% reduction in TNF-α, 71.43% reduction in IL-6). Mechanistically, dual-responsive MGF release synergized with the bioactive matrix to modulate the wound microenvironment and drive tissue regeneration. This study integrates natural pharmacotherapy with smart material design, offering a clinically translatable solution for diabetic wound management.