Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin‐Resistant S. aureus

Abstract Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non‐radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy‐Le) with the enhancement of non‐radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy‐Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet–triplet transition energies (Δ E S1–T1 ), promotes electron system crossing, enhances capacity of reactive oxygen species generation, and causes a significant increase in temperature by improving vibrational relaxation. SCy‐Le shows more than 99% bacterial killing rate against both methicillin‐resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria‐induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.