In Situ Oxygen-Releasing Microneedle Regulates Hypoxic Microenvironment and Promotes Angiogenesis Through MEK1/2-ERK1/2 Pathway for Diabetic Infected Wound Healing

Diabetic wound healing remains challenging due to microenvironmental complexities, including infection, hypoxia, and impaired angiogenesis. In this study, we established a diabetic rat wound model and found that the diabetic microenvironment significantly impaired angiogenesis, thereby delaying wound healing. To address this, a composite microneedle patch (M-TCHb MN) enabling in situ oxygen release was designed. The M-TCHb MN integrates TA-Ce metal phenol networks-encapsulated Hb nanoparticles (TA-Ce@Hb NPs) encapsulated in silk fibroin (SF) at needle tips with MXene nanosheets encapsulated in PVA at the base layer. In vitro studies confirmed that the base layer inhibits bacterial infection via PTT. TA-Ce@Hb NPs released from needle tips reduced oxidative stress and regulated macrophage polarization for inflammation resolution, while simultaneously catalyzing H 2 O 2 decomposition to generate O 2 . It works synergistically with Hb's oxygen release to reverse a hypoxic environment and promote angiogenesis. In vivo, M+TCHb MN suppressed infection, controlled inflammation, and enhanced angiogenesis. RNA sequencing analysis revealed that the relief of hypoxia enhances angiogenesis (upregulating the expression of VEGF) by activating the MEK1/2-ERK1/2 pathway. Collectively, M-TCHb MN represents an integrated strategy that combines antimicrobial, antioxidant, anti-inflammatory, and pro-angiogenic functions to synergistically accelerate diabetic wound healing, offering a translatable platform for clinical management.