ROS-Responsive Double-Layer Microneedles Enable Sequential Antibacterial and Immunomodulatory Therapy for Infected Wound Healing.

Abstract

The healing of chronically infected wounds is severely hindered by persistent inflammation, bacterial infection, and oxidative stress, posing great challenges to clinical therapy. To address these challenges, we designed a multifunctional dual-layer microneedles patch (MN@DOX+RES) featuring reactive oxygen species (ROS) responsiveness and dual drug delivery capabilities. This patch is engineered to deliver synergistic antibacterial, anti-inflammatory, and antioxidant effects, thereby promoting the healing of infected wounds.The dual-layer microneedles patch comprises a rapidly dissolvable HA backing layer loaded with DOX and a ROS-responsive tips layer composed of a crosslinked AHA-PBA/PVA matrix that encapsulates water-soluble RES inclusion complexes. A series ofexperiments was conducted to evaluate the mechanical strength, biocompatibility, antibacterial activity againstand, antioxidant performance, and macrophage polarization.evaluations were performed on rat models with infected skin wounds.The MN@DOX+RES microneedles exhibited strong skin penetration ability and excellent mechanical strength. It significantly inhibited bacterial growth, efficiently scavenged free radicals, reduced intracellular ROS levels, and enhanced M2 macrophage polarization., the patch accelerated wound closure, suppressed the inflammatory cytokine IL-6, enhanced IL-10 expression, and activated the Keap1/Nrf2/HO-1 antioxidant signaling pathway.This study proposes an innovative therapeutic strategy that combines dual-drug delivery, oxidative microenvironment regulation, and immune modulation to promote the healing of chronic infected wounds. The MN@DOX+RES microneedles system demonstrates great potential in overcoming clinical challenges associated with infection, inflammation, and the limitations of conventional therapeutic approaches.