Hostile microenvironment-driven oxygenator hydrogel with spatiotemporally feedback regulated hif-1α for accelerating diabetic wound healing

Abstract

Diabetic wounds remain notoriously intractable due to a hostile microenvironment characterized by hyperglycemia, hypoxia, and oxidative stress. However, existing therapies often lack the ability to autonomously and sustainably remodel this pathological niche. Herein, a smart nanoparticle-hydrogel composite (GC-PCCF) is engineered by integrating cascade enzymatic catalysis with a feedback‑regulated hypoxia-inducible factor-1α (HIF-1α) mechanism. The embedded GC liposomes comprehensively remodel the biological milieu via a glucose oxidase (GOx) and manganese dioxide (MnO₂) cascade. Specifically, GOx depletes excess glucose to mitigate hyperglycemic damage, while the MnO₂ nanozymes safely neutralize the catalytic byproducts and scavenge abundant endogenous ROS to directly oxygenate the wound. Concurrently, PCCF micelles respond to the GOx-driven pH drop to achieve spatiotemporally orchestrated, feedback‑controlled release of the prolyl hydroxylase inhibitor FG‑4592, which stabilizes HIF-1α and elegantly resolves the paradox wherein oxygen therapy alone accelerates HIF-1α degradation, thereby synergistically maximizing therapeutic outcomes. In vitro , GC-PCCF promotes M2 macrophage polarization, improves cellular metabolism, and facilitates endothelial angiogenesis under diabetic-mimetic stress. In vivo , the composite significantly accelerates full-thickness wound closure in db/db mice by coordinately modulating inflammation, proliferation, and remodeling phases, as further confirmed by transcriptomic analysis. With excellent biocompatibility, this autonomous microenvironment‑regulating platform offers a novel and safe therapeutic strategy for diabetic wounds.