pH/Hyal-Responsive Surface-Charge Switchable Electrostatic Complexation for Efficient Elimination of MRSA Infection

Methicillin-resistant Staphylococcus aureus (MRSA) has become a great threat to human health worldwide, makingnew effective antibacterial strategies urgently desired. In this study,a cationic pH-responsive delivery system (pHSM) was developed basedon poly(beta-amino esters)-methoxy poly(ethylene glycol), by whichlinezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibilityand stability of pHSM/LZD were further enhanced by adding low-molecular-weighthyaluronic acid (LWT HA) on the surface through electrostatic interactionto form pHSM/LZD@HA, of which the positive surface charges were neutralizedby LWT HA under physiological conditions. LWT HA can be degraded byhyaluronidase (Hyal) after arriving at the infection site. In vitro,pHSM/LZD@HA could rapidly change to being positively charged on thesurface within 0.5 h under acidic conditions, especially when Hyalwas present, thus promoting bacterial binding and biofilm penetrationof pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drugrelease behavior was also observed and it is beneficial for the comprehensivetreatment of MRSA infection in vitro and in vivo. Our study providesa novel strategy to develop a pH/Hyal-responsive drug delivery systemfor the treatment of MRSA infection.