Biofilm-microenvironment responsive hybrid micelle based on novel betaine derivative for enhanced delivery of honokiol against stubborn bacterial biofilms.

The development of conventional antibiotics is being severely challenged by the rise of bacterial resistance and the obstacle of biofilm-associated infections. Given their enhanced permeability, nano micelles have emerged as a widely utilized platform for the delivery of hydrophobic drugs. In this study, a novel material named BS-12-PEG-OH (PB12) was synthesized, and an intelligent nanoplatform was successfully developed through thin film dispersion method by co assembling vitamin E polyethylene glycol succinate (TPGS) with PB12 into hybrid micelles via thin film dispersion method, thereby enabling the encapsulation of Honokiol (designated as HK@PB12/TPGS Ms). The hybrid micelle can effectively penetrate the extracellular polymeric substance barrier of the biofilm. Upon reaching the acidic microenvironment, it responsively releases dodecyl dimethyl betaine (BS-12) and honokiol (HK), thus eliminating the biofilm structure and killing the embedded bacteria. Under acidic conditions, HK@PB12/TPGS Ms achieved a substantial bacterial reduction of 9.60 log10 CFU/ml. Furthermore, under the acidic condition of the biofilm microenvironment, they effectively cleared 83.32 % of the biofilm and reduced the embedded S. aureus by 3.75 log10 CFU/ml. The results indicate that the HK@PB12/TPGS Ms could effectively penetrate Staphylococcus aureus biofilms, disrupt their structure, and eliminate the bacteria inside the biofilm, hence preventing new infections and providing a novel therapeutic strategy for combating stubborn biofilm-associated infections.