Dual-Hyperbranched Strategy Enabling Remarkable Selectivity and Broad-Spectrum Antibacterial and Anticancer Activities

Microbes, including both Gram-positive and Gram-negative bacteria, contribute to tumor initiation, progression, and metastasis. This complex association requires agents for a concurrent broad-spectrum antibacterial and anticancer therapy. Herein, we report a novel dual-hyperbranched strategy that constructs host-defense peptide mimics with a hydrophobic aliphatic acid interlayer and an outer hydrophilic polylysine shell to address this challenge. This unique structure resulted in a shared membranolytic mechanism targeting membranes with excessive negative charges, achieving potent activity against various bacteria and cancer cells. More importantly, the dual-hyperbranched strategy reduces toxicity significantly, which was attributed to the restriction of the mobility of hydrophobic segments. In vivo experiments further confirmed these concurrent activities and safety to normal tissues. Collectively, this work provides a new strategy for the design of cationic HDP-mimetic polymers and highlights their potential for integrated antibacterial and anticancer therapy.