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 antiplanktonic 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.