Bacteria‐Responsive Multidrug Delivery Nanosystem for Combating Long‐Term Biofilm‐Associated Infections

Abstract Microbial biofilm formation on implantable devices causes chronic infections that cannot be treated with existing antimicrobials. Quorum sensing inhibitors (QSIs) have recently emerged as novel antimicrobials for the prevention of biofilm formation. But blocking QS alone is insufficient to inhibit biofilm‐associated chronic infections. Herein, chitosan hollow nanospheres are capped by bacteria‐responsive β‐casein to form a synergistic antifouling nanosystem consisting of a QSI and bactericide. β‐casein is degraded by protease in a bacteria‐colonized microenvironment in situ thus, QSI and bactericide are released sequentially. The release of QSI sensitises bacteria effectively through reduction of surface hydrophobicity, eDNA content, and lipopolysaccharide production in biofilms, amplifying the chemotherapeutic action of the bactericide. Compared to the uncoated surface, the coated surface inhibits biofilm formation and removes preformed biofilms of Pseudomonas aeruginosa PAO1 and methicillin‐resistant Staphylococcus aureus by 1.8 logs and 1.9 logs of biomass inhibition, respectively. The coated catheters are found to stay clean for 30 days under artificial urine flow, while the uncoated catheters are clogged by bacterial biofilms within 5 days. Finally, the long term antifouling activity in vivo is confirmed. Overall, the nanosystem is devoted to making urinary catheters resistant to bacterial biofilm formation for the long term.