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

Methicillin-resistant (MRSA) has become a great threat to human health worldwide, making new effective antibacterial strategies urgently desired. In this study, a cationic pH-responsive delivery system (pHSM) was developed based on poly(β-amino esters)-methoxy poly(ethylene glycol), by which linezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibility and stability of pHSM/LZD were further enhanced by adding low-molecular-weight hyaluronic acid (LWT HA) on the surface through electrostatic interaction to form pHSM/LZD@HA, of which the positive surface charges were neutralized by LWT HA under physiological conditions. LWT HA can be degraded by hyaluronidase (Hyal) after arriving at the infection site. In vitro, pHSM/LZD@HA could rapidly change to being positively charged on the surface within 0.5 h under acidic conditions, especially when Hyal was present, thus promoting bacterial binding and biofilm penetration of pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drug release behavior was also observed and it is beneficial for the comprehensive treatment of MRSA infection in vitro and in vivo. Our study provides a novel strategy to develop a pH/Hyal-responsive drug delivery system for the treatment of MRSA infection.