Bergapten-Loaded Multifunctional Soluble Microneedle Patch with Bidirectional ROS Regulation and Pyroptosis Suppression Accelerates Chronic Infected Wound Healing via the Nrf2-NF-κB-NLRP3 Axis.

Abstract

Chronic infected wounds suffer from impaired tissue healing due to bacterial biofilm formation, an imbalanced inflammatory microenvironment, excessive accumulation of reactive oxygen species (ROS) and pyroptosis triggered by GSDMD activation. Herein, a multifunctional soluble microneedle system (ACBP@MN) that integrates ultrathin Au/Cu nanosheets loaded with the traditional Chinese medicine monomer Bergapten (BP) is developed. This system enables bidirectional ROS regulation, synergizing catalytic ROS generation with antioxidant defense activation and pyroptosis pathway modulation to break the infection-inflammation-oxidative damage cycle. Our results confirmed that in a S. aureus-infected murine wound model, ACBP@MN showed superior antibacterial, anti-inflammatory, angiogenic, and regenerative outcomes, with excellent biosafety. During the early infection phase, ACBP@MN exerts potent bactericidal effects via peroxidase-like activity and glutathione depletion. RNA sequencing revealed that it also disrupts bacterial biofilm formation and key metabolic pathways, including the TCA cycle and BCAA metabolism. At the inflammatory stage, ACBP@MN reduces oxidative stress and persistent inflammation by enhancing the activities of catalase and superoxide dismutase enzymes and upregulating the Nrf2/HO-1 pathway. Subsequently, Nrf2 activation indirectly inhibits the NF-κB pathway, leading to suppressed NLRP3 inflammasome activation and prevention of GSDMD-mediated pyroptosis. In conclusion, this study proposes an innovative strategy for chronic infected wound management through the rational design of multifunctional composite microneedle systems.