Self-assembled copper-amino acid nanoleaves for targeted treatment of deep-seated bacterial infections via chemodynamic therapy and cuproptosis-like death

Abstract

Transition metal ions such as Cu²⁺ are promising broad-spectrum bactericidal agents. However, transition metal ions are not used to treat deep-seated bacterial infections in clinic owing to easy deactivation by proteins and lack of targeting ability. Herein, hyaluronic acid (HA)-modified copper-N-acetyl-l-cysteine (NAC) nanoleaves (CNH NLs) are developed to treat deep-seated bacterial infections by targeted delivery of Cu²⁺ to infection sites. Cu-NAC nanoleaves (CN NLs) can be synthesized by coordinate assembly of Cu²⁺ and NAC, which are further coated with HA to obtained CNH NLs with targeting ability. CNH NLs are stable in neutral physiological environment, while can be easily decomposed in acidic infection sites, leading to rapid release of Cu²⁺. The released Cu²⁺ disrupts bacterial membranes, depletes glutathione, generates reactive oxygen species (ROS), and induces cuproptosis-like bacterial death, exhibiting potent activity against both planktonic bacteria and biofilms. The targeted accumulation and excellent therapeutic efficacy of CNH NLs is further confirmed on murine bacterial keratitis and pneumonia models, highlighting their therapeutic potential for deep-seated infections.