ROS-responsive nanoassembly co-delivering chlorogenic acid and copper accelerates healing of infected burns via oxidative stress mitigation and macrophage M2 polarization

Burns catastrophically compromise the skin barrier, driving impaired healing, infection susceptibility, and regenerative failure, primarily through dysregulated inflammation, immune dysfunction, and overwhelming oxidative stress. While reactive oxygen species (ROS) mediate essential host defense, their pathological excess necessitates targeted modulation for burn repair. We engineered a ROS-responsive nanoassembly (PTC@Cu NPs) for co-delivering chlorogenic acid (CGA) and copper ions (Cu 2+ ). Synthesizing the amphiphilic polymer mPEG-TK-CGA (PTC) via a ROS-cleavable thioketal linker enabled self-assembly with Cu 2+ into NPs. This system achieves triggered release specifically within high-ROS burn sites. CGA and Cu 2+ act synergistically to potently scavenge ROS, polarize macrophages to a pro-regenerative M2 phenotype, and thereby ameliorate oxidative damage, infection, and healing deficits in deep partial-thickness burns. In vitro and in vivo studies demonstrate PTC@Cu NPs significantly suppress apoptosis, enhance cell migration, exert potent antibacterial effects, and markedly accelerate healing. These comprehensive therapeutic benefits are mechanistically underpinned by dual ROS reduction and macrophage M2 polarization. Collectively, this platform presents a promising strategy for infected deep burn wounds by simultaneously targeting oxidative damage, microbial infection, and impaired tissue repair.