De Novo Development of Bioresponsive Nanoparticles With Antimicrobial Activity to Treat Bacterial Infections

ABSTRACT Bacterial infections pose a major global health threat, exacerbated by the rise of antimicrobial resistance. However, antibiotics are losing efficacy due to the emergence of multidrug‐resistant pathogens. Here, we reported a bioresponsive nanoparticle with antimicrobial activity and targeting effect to bypass the antimicrobial resistance and to improve the bacterial infections treatment. We established a mini library of quaternary ammonium compounds, and screened the N‐benzyl‐N‐(n‐(4‐formyl‐3,5‐dimethoxyphenoxy)decyl)‐N,N,N,N‐tetramethylhexane‐1,6‐diaminium (BTA‐10) that enabled high antimicrobial activity in vitro and safety in vivo, which was selected to conjugate with the poly(ethylene glycol) (PEG) via pH‐responsive bond to synthesize amphiphilic copolymer for preparation of polymeric micelle, followed by decorating with anti‐ICAM‐1 as targeting ligand via click chemistry, resulting in bioresponsive nanoparticle (NPs‐anti‐ICAM‐1). The anti‐inflammatory drug TPCA‐1 was physically loaded to enhance the therapeutic efficacy, to prepare the final therapeutic (TPCA‐1@NPs‐anti‐ICAM‐1). Upon intravenous injection, TPCA‐1@NPs‐anti‐ICAM‐1 can specifically target to the site of infection, and release the cargos (BTA‐10 and TPCA‐1) by responding to acids in the infection microenvironment. The in vivo studies demonstrated that TPCA‐1@NPs‐anti‐ICAM‐1 showed high therapeutic efficacy for acute lung infection and peritonitis in mouse. In summary, we reported a de novo‐designed bioresponsive nanoparticle with antimicrobial activity, offering a promising approach to combat bacterial infections.