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

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.