NIR-Activated ROS/NO Cascade Nanocomposite Rewires Bacterial Redox Defense for Synergistic Eradication of Pseudomonas aeruginosa Wound Infection

Pseudomonas aeruginosa wound infections remain difficult to eradicate because biofilm formation and bacterial redox-adaptive defenses weaken antibacterial efficacy and delay tissue repair. In this study, we reported a near-infrared (NIR)-activated reactive oxygen species (ROS)/ nitric oxide (NO) cascade nanocomposite, UCeSi-L@CA, designed to amplify oxidative/nitrosative antibacterial stress while promoting infected wound healing. UCeSi-L@CA was constructed from Ce6-loaded mesoporous silica-coated upconversion nanoparticles, with L-arginine conjugated through surface carboxyl groups and cinnamaldehyde loaded into the mesopores. Upon NIR irradiation, upconversion nanoparticles activated Ce6 to generate abundant ROS. Cinnamaldehyde exerted direct antibacterial activity and inhibited glutathione-mediated ROS scavenging, thereby sustaining ROS accumulation and weakening bacterial antioxidant defense. The accumulated ROS further triggered NO production from L-arginine, establishing a ROS/NO cascade in which ROS and NO cooperatively damaged bacterial membranes, enhanced lipid peroxidation, and induced efficient bacterial killing. Beyond antibacterial activity, NO also contributed to infected tissue repair. In vitro, UCeSi-L@CA + NIR showed excellent killing against planktonic P. aeruginosa, effectively inhibited biofilm formation, eradicated bacteria within established biofilms, and suppressed biofilm regrowth. In the P. aeruginosa-infected wound model, UCeSi-L@CA + NIR markedly reduced local bacterial burden, attenuated infection-associated inflammation, accelerated wound closure, and promoted tissue repair, with favorable biocompatibility in vitro and in vivo. This nanocomposite presents a non-antibiotic nanotherapeutic strategy integrating NIR-triggered ROS generation, cinnamaldehyde-mediated GSH-defense inhibition, and L-arginine-derived NO release for treating refractory biofilm-associated wound infections.