The primary challenges in repairing multidrug-resistant bacteria (MDRB) infected wounds arise from antibiotic resistance, insufficient vascularization, and disrupted cellular energy metabolism. Herein, we develop an infection-responsive antibacterial hydrogel (CBGCT) with mitochondria-mimicking bioenergy-supplying capabilities for vascularized wound repair. The CBGCT hydrogel was composed of an individually photo-crosslinkable boronized poly(citrate-ε-polylysine) matrix, reinforced with copper ion-tannic acid nanosheets (Cu@TA) and guar gum. The CBGCT hydrogel demonstrated enhanced antimicrobial activity and ROS scavenging in response to acidic pH and high ROS levels. The pH-responsive degradability of Cu@TA nanosheets enabled the cascaded controlled-release of copper ions and tannic acid from the CBGCT hydrogel, thereby enhancing angiogenesis and anti-inflammatory effects. Additionally, The citrates generated during the degradation of CBGCT hydrogel can also accelerate the tricarboxylic acid cycle, elevating mitochondrial membrane potential and intracellular ATP levels (1.4-fold higher than the negative control group), which ensured a sustained supply of bioenergy for cellular physiological processes. Ultimately, the CBGCT hydrogel effectively eradicated bacterial infections, modulated the immunological environment by suppressing the expression of inflammatory factors, and enhanced angiogenesis and collagen deposition, thereby facilitating the repair and reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)-infected mice wounds (closure rate of 94.3 % by day 14). From the point of regulating cellular energy metabolism and angiogenesis, this work provides a good strategy to develop smart responsive hydrogel with precise bioactivities for repairing infection-related tissue injury. STATEMENT OF SIGNIFICANCE: The microenvironment-responsive bioactive hydrogel with activated cellular ability has become promising for treating multidrug-resistant bacteria (MDRB) infected wounds. However, activating disrupted intracellular metabolism with enhanced angiogenesis while keeping infection-responsive bioactivity remains a critical challenge. Herein, we develop a microenvironment-responsive antibacterial hydrogel (CBGCT) with mitochondria-mimicking bioenergy-supplying capabilities for vascularized wound repair. CBGCT possessed pH-ROS responsive release of copper ions and polycitrates, thereby enhancing the tricarboxylic acid cycle, elevating mitochondrial membrane potential and intracellular ATP levels, and accelerating the angiogenesis and wound repair. From the point of regulating cellular energy metabolism and angiogenesis, this work provides a strategy to develop smart responsive hydrogel with precise bioactivities for repairing infection-related tissue injury.
