摘要The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections.Phytochemical-based nanoplatform is a promising emerging approach for treatment of biofilm infection.However,their therapeutic efficacy was restricted by the low drug loading capacity and lack of selectivity.Herein,we constructed a surface charge adaptive phytochemical-based nanoparticle with high isoliquiritigenin(ISL)loading content for effective treatment of MRSA biofilm.A dimeric ISL prodrug(ISL-G2)bearing a lipase responsive ester bond was synthesized,and then encapsulated into the amphiphilic quaternized oligochitosan.The obtained ISL-G2 loaded NPs possessed positively charged surface,which allowed cis-aconityl-D-tyrosine(CA-Tyr)binding via electrostatic interaction to obtain ISL-G2@TMDCOS-Tyr NPs.The NPs maintained their negatively charged surface,thus prolonging the blood circulation time.In response to low pH in the biofilms,the fast removal of CA-Tyr led to a shift in their surface charge from negative to positive,which enhanced the accumulation and penetration of NPs in the biofilms.Sequentially,the pH-triggered release of D-tyrosine dispersed the biofilm and lipase-triggered released of ISL effectively kill biofilm MRSA.An in vivo study was performed on a MRSA biofilm infected wound model.This phytochemical-based system led to～2 log CFU(＞99％)reduction of biofilm MRSA as compared to untreated wound(P＜0.001)with negligible biotoxicity in mice.This phytochemical dimer nanoplatform shows great potential for long-term treatment of resistant bacterial infections.