Kinsenoside‐Loaded Microneedle Accelerates Diabetic Wound Healing by Reprogramming Macrophage Metabolism via Inhibiting IRE1α/XBP1 Signaling Axis

Abstract Continuously bacterial infection, undue oxidative stress, and inflammatory responses in the skin tissue microenvironment determine the delayed healing outcome of diabetic wounds, which remain a tough clinical challenge and need multifaceted therapeutic strategies. In this work, HA‐ADH/HA‐QA‐ALD‐based hydrogel microneedle (HAQA‐MN) with antimicrobial and antioxidative activities incorporating kinsenoside (KD) coated with macrophage membrane (M‐KD) targeting inflammation relief is developed to improve the cutaneous micro‐niche. KD is observed to trigger trimethylamine N‐oxide‐irritated proinflammatory macrophages repolarization from M1 state to anti‐inflammatory M2 phenotype, and the underlying mechanism is due to drug‐induced IRE1α/XBP1/HIF‐1α pathway suppression, accompanied by diminution of glycolysis and enhancement of oxidative phosphorylation, resulting in proinflammatory cascade inhibition and anti‐inflammatory signaling enhancement. The hydrazone cross‐linked HAQA‐MN possesses favorable biocompatibility, self‐healing, controlled release of M‐KD and excellent mechanical properties. Moreover, the MN patch remarkedly restrains the survival of E. coli and S. aureus and eliminates hydrogen peroxide to preserve cellular viability. Notably, M‐KD@HAQA‐MN array effectively ameliorates cutaneous inflammation and oxidative stress and facilitate angiogenesis and collagen deposition, thereby accelerating tissue regeneration of diabetic mice with a full‐thickness skin defect model. Collectively, this study highlights a multifunctional MN platform as a promising candidate in clinical application for the treatment of diabetic wounds.