Trifunctional nanoparticles accelerate diabetic wounds healing via oxidative-immune-vascular coordination

Abstract

Current treatments for diabetic wounds remain a critical clinical challenge due to their suboptimal therapeutic efficacy. Patients with diabetic wounds suffer from prolonged inflammation, ROS overproduction, and impaired angiogenesis, creating a self-perpetuating healing cycle. Here, we report a biomimetic trifunctional nanoparticle comprising nanozymes (Heme@BSA), a ROS-scavenging core, a pro-angiogenic bFGF payload, and a pH-responsive H₂S-eluting MnS shell. This design enables spatiotemporal synergism to mitigate the self-perpetuating healing cycle in diabetic wounds, via converting ROS into O₂; microenvironment- triggered H₂S release to ameliorate excessive inflammation; and sustained bFGF delivery to promote cell proliferation and migration, facilitate well-organized collagen realignment, and expedite epithelialization. Comprehensive mechanistic analyses reveal that nanozyme- transmuted O₂ reduces HIF-1α-stabilized bFGF-mediated revascularization; H₂S-driven Nrf-2 activation and HO-1 upregulation effectively assist the nanozyme in overcoming the acute ROS microenvironment via robust antioxidant and anti-apoptotic capabilities; and bFGF-supported proliferation effectively amplifies H₂S-initiated macrophage polarization in the wound core. Collectively, our investigation offers an oxidative-immune-vascular coordinated approach for diabetic wound repair, highlighting its translational potential in the management of diabetic wounds.