Hydrogel Delivery Systems for Diabetic Wound Healing: Design Paradigms for Stimuli-Responsive Release, Nanocomposite Engineering, and Bioactive Self-Assembly

Diabetic wounds are sustained by a complex and dynamic pathological network involving hyperglycemia, persistent inflammation, oxidative stress, impaired angiogenesis, extracellular matrix degradation, and microbial biofilms, which collectively limit the effectiveness of conventional passive dressings. This review summarizes recent advances in hydrogel delivery systems for diabetic wound healing and classifies them according to the principal strategy by which therapeutic performance is integrated into the hydrogel platform, focusing on stimuli-responsive hydrogels, nanocomposite hydrogels, and natural bioactive self-assembled hydrogels. Stimuli-responsive hydrogels exploit wound-associated cues, including reactive oxygen species, pH, glucose, matrix metalloproteinases (MMPs), and temperature, to enable on-demand and spatiotemporally controlled therapeutic delivery. Building on this precise release control, nanocomposite hydrogels integrate lipid-based nanocarriers, bio-derived vesicles, or inorganic nanomaterials into macroscopic hydrogel networks to improve cargo stability, local retention, and sustained delivery. Natural bioactive self-assembled hydrogels further broaden hydrogel design by extending it from therapeutic cargo regulation and delivery to the direct participation of bioactive molecules in material construction. Through non-covalent interactions, these molecules function as both therapeutic agents and structural units, integrating bioactivity with hydrogel formation. Collectively, these strategies progressively integrate controlled release, enhanced therapeutic delivery, and bioactive material construction to address the multifaceted pathological barriers of diabetic wounds, including inflammation, oxidative stress, infection, impaired angiogenesis, and defective tissue regeneration. This review also discusses the current challenges and future perspectives of these hydrogel delivery systems and aims to provide valuable reference for the rational design and clinical translation of advanced hydrogel delivery systems for diabetic wound healing.