Surface charge-convertible quaternary ammonium salt-based micelles for in vivo infection therapy

Quaternary ammonium salts (QASs) are excellent candidates for treating stubborn bacterial infections caused by biofilms due to their high sterilization efficiency and potential inhibition of the development of drug resistance. However, the inherent toxicity of QASs, including cytotoxicity, protein absorption and hemolysis, severely limits their applications in vivo. Herein, a charge-convertible quaternary ammonium salt-based micelle (QAS-SL@CM) was constructed by co-assembly of two amphiphiles with opposite charges and shell cross-linking strategy. The toxicity of the QAS-SL@CM could be greatly reduced towards human cells contrast to the corresponding QASs. By response to the acidic environment at infection sites, the surface charge of QAS-SL@CM could be immediately changed to positive and then target to negatively charged bacteria. Furthermore, beta-thiopropionate bonds on QAS-SL@CM could also be disintegrated under acid environment to release QASs to kill bacteria. Importantly, the QAS-SL@CM showed significant therapeutic effect in mice subcutaneous abscesses models without interference with normal cells. Therefore, a surface adaptive micelle constructed by charge-convertible strategy has been developed to overcome the cytotoxicity of QASs, and could intelligently respond to the microenvironment of infected wound for in vivo infection therapy, which shows promising application in clinic.& nbsp; (c) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.