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

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.