Sequence-dependent self-assembly and carbon monoxide release of peptide-flavonoid conjugates for infected wound healing.

Abstract

Multidrug-resistant bacterial infection has become increasingly severe due to the abuse of antibiotics. Recently, carbon monoxide (CO)-based gas therapy has stood out as a novel strategy to overcome antimicrobial resistance and clear infection. However, the application is hindered by the reactive gas nature and poor precise loading. Herein, we developed a peptide-based delivery strategy by covalently binding the photo-sensitive CO donor 3-hydroxylflavone (3-HF) to the N-terminus of antimicrobial peptides (AMPs), achieving controllable and quantitative loading of CO donors. Meanwhile, by altering the amino acid sequences of AMPs, constitutionally isomeric AMP-HF conjugates underwent distinct assemble behaviors and formed different morphologies, leading to distinct light-triggered CO-releasing patterns. In vitro experiments revealed that the sequence-dependent CO-releasing behavior could enhance the antibacterial and anti-inflammatory capacity of AMP-HF conjugates to different extents. In vivo results further confirmed that AMP-HF conjugates could differentially eliminate bacteria and reconstruct the inflammatory environment at the infected site to accelerate the wound healing process.