Phytochemical nanozymes reprogram redox for balanced antimicrobial and regenerative therapy in acute and chronic diabetic wounds

Abstract

Chronic diabetic wounds are characterized by persistent oxidative stress and microbial infections, leading to delayed healing and tissue repair. While elevated reactive oxygen species (ROS) levels can provide bactericidal effects, uncontrolled oxidative stress simultaneously impairs tissue regeneration. Thus, precise redox modulation that balances antimicrobial efficacy with tissue regeneration is critical for effective wound therapy. Herein, we developed a phytochemical nanozymes system by integrating ferulic acid (FA) with cerium oxide nanoparticles (CeO₂), enabling precise redox modulation to balance antimicrobial efficacy with tissue regeneration. Structural analysis confirmed the uniform dispersion and pH-responsive release of FA and Ce ions, facilitating targeted redox modulation. The FA-CeO₂ nanozymes exhibited potent antioxidant activity through Ce³⁺/Ce⁴⁺ cycling and FA-mediated radical scavenging, effectively mitigating oxidative stress while promoting bacterial clearance against S. aureus and E. coli. Furthermore, FA-CeO₂ significantly enhanced Nrf2/HO-1 pathway activation, leading to upregulated VEGF/CD31 expression, accelerated cell proliferation, and enhanced collagen deposition in vitro. In vivo, FA-CeO₂ facilitated wound closure, reduced bacterial burden, and improved tissue regeneration in acute and diabetic wound models, with minimal cytotoxicity and excellent biocompatibility. These findings highlight the critical role of precise redox modulation in balancing antibacterial and regenerative therapy, positioning phytochemical nanozymes as a dual-modality platform for effective wound therapy and advancing nanomedicine strategies targeting oxidative stress and tissue repair.