A Sprayable Nucleic Acid Hydrogel for Diabetic Wound Healing via Immunomodulation and Angiogenesis

Abstract Diabetic wounds (DWs), a prevalent form of chronic wound, are highly susceptible to infection and impaired healing due to immune dysregulation, persistent inflammation, and abnormal angiogenesis, which can ultimately result in increased disability, mortality, and healthcare burdens. Uncontrollable bleeding and coagulation disorders following severe trauma present major challenges for existing hemostatic agents. To address these issues, a multifunctional nucleic acid hydrogel (TR21@TS) is developed by integrating microRNA‐21‐5p‐loaded tetrahedral framework nucleic acids (tFNAs) with tannic acid (TA) and tetra‐polyethylene glycol (4‐PEG) derivatives, and the hybrid hydrogel exhibited wet adhesiveness, mechanical robustness, sprayability, and injectability. Compared to commercial products, the hydrogel showed superior hemostatic performance in a rat acute liver hemorrhage model and accelerated wound closure in full‐thickness DWs. Both in vitro and in vivo studies revealed that the hydrogel reprogrammed macrophage polarization, attenuated oxidative stress and inflammation via nuclear factor kappa B (NF‐κB) inhibition, and enhanced angiogenesis through protein kinase B (AKT) pathway activation, thereby facilitating tissue regeneration. This functionalized nucleic acid hydrogel represents a promising therapeutic strategy for addressing uncontrolled hemorrhage and chronic diabetic wound healing.