Inflammatory Microenvironment-Responsive Nanomotors with NIR Photothermal Effect for Deep Inflammation Elimination and Infection Inhibition

The infected chronic wound area has a unique microenvironment featuring hypoxia, excessive reactive oxygen species (ROS), and inflammatory conditions. Bacteria-formed biofilms limit the anti-inflammation efficiency of most therapeutics by hindering their penetration into deep infected wound tissues and increasing drug resistance. The unitary modulation of pro-inflammatory M1 macrophage polarization cannot relieve inflammation immediately. Here, the “all in one” folic acid-modified small organic molecule-based nanoparticles (2TT-mC6B@CeO₂@FA, PCFs) are developed, which possess dual-targeting to bacteria and M1 macrophages, double modulation to M1 macrophages, photothermal therapy (PTT), and enzymatic-like activities. Based on the considerable catalase- and superoxide dismutase-like activities, PCFs can efficiently scavenge ROS and produce oxygen (O₂). The generated O₂ can automatically drive PCFs movement as nanomotors to further promote deep penetration and rescue hypoxia. The scavenging of ROS promotes M1 macrophages polarized into anti-inflammatory M2 macrophages. The study also identifies that FA-modified PCFs can target bacteria and M1 macrophages to selectively eliminate M1 macrophages and bacteria through PTT, which relieves inflammation and chronic wound healing. Transcriptome analysis confirms that PCFs inhibit the expression of inflammatory-related genes while increasing the expression of anti-inflammatory cytokines. In vivo experiments identify that PCFs benefit neovascularization in neonatal tissues and tissue generation at wound sites.