A dynamically coordinated bioactive MOF-hydrogel system for ternary microenvironment reprogramming in MRSA-infected diabetic wounds

Abstract

Due to a persistent inflammatory response, excessive accumulation of ROS, and MRSA infection, the repair of diabetic chronic wounds faces severe challenges. Here, an intrinsically bioactive MOF-hydrogel system (SR@P/L) was designed to accelerate wound healing by reprogramming the multidimensional microenvironment. This system was based on poly (lipoic acid) and chitosan derivatives and was loaded with a novel strontium-rosmarinic acid MOF (SR-MOF). Dynamic disulfide, coordination, and hydrogen bonds formed a stable supramolecular network. Characterization revealed that the SR@P/L hydrogel displayed strong tissue adhesion, self-healing, and glucose-assisted stability. Moreover, it exhibited potent intrinsic antibacterial and antioxidant activities, as well as rapid hemostatic activity. Mechanistically, the SR@P/L hydrogel induced macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype through a ternary synergistic reprogramming effect of “immunomodulation, angiogenesis, and neurogenesis” and regulated the paracrine “cross talk” among multiple cell types. It also significantly enhanced the angiogenic capacity of vascular endothelial cells and the regenerative function of Schwann cells. In diabetic rats and large-animal models (mini-Bama pigs) with MRSA-infected wounds, the SR@P/L hydrogel promoted wound healing by accelerating granulation tissue formation and collagen remodeling. RNA-seq further revealed that the hydrogel promoted skin closure and functional recovery by coordinating adaptive immunity and tissue remodeling pathways. This multidimensional strategy presents a new design concept for treating refractory chronic wounds.