Self-Assembly of Antimicrobial Peptide-Based Micelles Breaks the Limitation of Trypsin

Abstract

Targeting the limitation of antimicrobial peptides (AMPs) application <i>in vivo</i>, self-assembled AMPs library with specific nanostructures is expected to gradually overtake monomer AMPs libraries in the future. Peptide polymers are fascinating self-assembling nanoscale structures that have great advantage in biomedical applications because of their satisfactory biocompatibility and versatile properties. Herein, we describe a strategy for inducing the self-assembly of T9W into nanostructured antimicrobial micelles with evidently improved pharmacological properties, that is, PEGylation at the C-terminal of T9W (CT9W₁₀₀₀), an antibacterial biomaterial that self-assembles in aqueous media without exogenous excipients, has been developed. Compared with parental molecular, the CT9W₁₀₀₀ is more effective against <i>Pseudomonas aeruginosa</i>, and its antibacterial spectrum had also been broadened. Additionally, CT9W₁₀₀₀ micelles had higher stability under salt ion, serum, and acid-base environments. Importantly, the self-assembled structure is highly resistant to trypsin degradation, probably allowing T9W to be applied in clinical settings in the future. Mechanistically, by acting on membranes and through supplementary bactericidal mechanisms, CT9W₁₀₀₀ micelles contribute to the antibacterial process. Collectively, CT9W₁₀₀₀ micelles exhibited good biocompatibility <i>in vitro</i> and <i>in vivo</i>, resulting in highly effective treatment in a mouse acute lung injury model induced by <i>P. aeruginosa</i> PAO1 without drug resistance. These advances may profoundly accelerate the clinical transformation of T9W and promote the development of a combination of peptide-based antibiotics and PEGylated nanotechnology.