Dual-metallic porphyrinic MOFs with pH/ROS-responsive release for antibacterial and antioxidant therapy of diabetic infected wounds
Rationale : Chronic diabetic wounds are complicated by multidrug-resistant (MDR) infections and a deleterious oxidative microenvironment, rendering single-target therapies ineffective. This study aimed to develop a smart, dual-metal-organic framework (MOF) nanoplatform (PCNZnCy) capable of microenvironment-responsive, coordinated antibacterial, antioxidant, and pro-regenerative therapy for infected diabetic wounds. Methods : The nanoplatform PCNZnCy was constructed by integrating the natural flavonoid chrysin into a zinc-doped porphyrinic MOF (PCN-224), enabling pH-and reactive oxygen species (ROS)-triggered co-release of Zn² ⁺ and chrysin. Antibacterial and anti-biofilm activity was assessed against biofilm-embedded MDR pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA). Antioxidant and signaling effects were evaluated by measuring ROS scavenging, mitochondrial function, endothelial cell proliferation, and activation of Nrf2/HO-1, STAT3, and Akt pathways, with confirmation using the Nrf2 inhibitor ML385. To assess efficacy and safety in a clinically meaningful setting, we used a diabetic murine wound model infected with P. aeruginosa and a systems-level transcriptomic analysis to capture the broader tissue response. Results : We found that PCNZnCy showed strong synergistic antibacterial activity against MRSA and PA. Beyond that, it scavenged excess ROS, triggered Nrf2/HO-1 signaling, modulated STAT3 and Akt signaling, preserved mitochondrial health, and spurred endothelial cell growth. In diabetic mice, wounds healed faster, with improved collagen deposition and increased formation of new blood vessels, while the compound remained safe. RNA-seq data underscored a decisive move from pro-inflammatory to pro-regenerative gene expression. Conclusions : PCNZnCy adapts to the wound's specific microenvironment, enabling it to kill bacteria, reduce oxidative stress, and promote tissue regeneration. In the infected diabetic models, it worked consistently well. This makes it a strong candidate for multifactorial, complex wound pathologies, in which multiple complications overlap.