Near-infrared light-triggered in situ self-assembly nanomedicine for treating antibiotic-resistant bacterial infection

Antibiotic-resistant bacterial infections are increasing at an alarming rate, posing a significant threat to global health and highlighting the urgent need for innovative therapeutic strategies. Herein, we developed a near- infrared (NIR) photoactivatable amphiphilic precursor molecule of peptide-vancomycin conjugate (PFTV), which could in situ self-assemble into a nanogermicidal agent on bacterial surfaces upon exposure to NIR light. This approach aimed to effectively treat infections caused by vancomycin-resistant Enterococcus (VRE). Our findings indicated that the in situ self-assembly of PFTV triggered by NIR light demonstrated superior anti- planktonic activity compared to free vancomycin, with the minimum inhibitory concentration reduced by two orders of magnitude. Additionally, this strategy enhanced PFTV penetration and removal of VRE biofilms, achieving a bacterial killing efficiency of 99%. Mechanistic studies revealed that the combination of PFTV and NIR light treatment eradicated antibiotic-resistant bacteria via two main actions: membrane perturbation and disruption of cellular homeostasis. Furthermore, the in situ self-assembly of PFTV upon NIR light irradiation demonstrated significant therapeutic efficacy in treating VRE-induced infections and accelerating wound healing in vivo by mitigating inflammation responses and promoting neovascularization. This work has reported an on- demand activated strategy to facilitate peptide-antibiotic conjugate in situ self-assembly into a multivalent nanoantibacterial agent, which could provide novel paradigm for targeted drug delivery and combating multidrug-resistant pathogens.