Facile Synthesis of Zn²⁺‐Based Hybrid Nanoparticles as a New Paradigm for the Treatment of Internal Bacterial Infections

Abstract Transition metal ions such as Ag⁺, Cu²⁺, and Zn²⁺ are utilized as sterile agents thousands of years ago. Unfortunately, these metal ions in the form of traditional metal or metal oxide nanoparticles cannot be directly medicated into human body due to the potential toxicity. Herein, novel Zn²⁺–ε‐poly(l‐lysine) (EPL)–protocatechuic aldehyde (PCA)‐based hybrid nanoparticles (ZEP NPs) with on‐demand release capability are synthesized for the first time by one‐step coordination self‐assembly of Zn²⁺, EPL, and PCA to address this issue. The ZEP NPs can effectively adhere on bacterial cells and release Zn²⁺ in situ due to the decomposition of ZEP NPs in acidic infection microenvironment. More importantly, ZEP NPs exhibit excellent bactericidal ability in a protein‐rich environment, in which free Zn²⁺ completely loses its bactericidal ability. The excellent bactericidal effect of ZEP NPs is confirmed in a skin infection model and a lung infection model, demonstrating the great potential to deal with internal infections. Meanwhile, ZEP NPs exhibit negligible toxicity since the dose of Zn²⁺ can be significantly reduced compared to the commercial zinc oxide nanoparticles (ZnO NPs). The outstanding bactericidal ability as well as negligible toxicity of ZEP NPs makes it ideal candidate of next generation antibacterial agents in treating internal infections.