Functional Self-Similar Polyether–Polyester Mimicking Host Defense Peptides Enable Prolonged Antimicrobial Activity

Maintaining a potent antimicrobial efficacy over extended periods is critical for treating bacterial infections associated with chronic wounds. Although host defense peptides (HDPs) and their cationic polymer mimics are effective against drug-resistant bacteria, their long-term performance is often compromised by protease-mediated degradation. Herein, we report a series of cationic polyether-polyester-mimicking HDPs exhibiting consistently potent antimicrobial efficacy and excellent biocompatibility in both intact and degraded forms, termed functional self-similar polymers. The optimal copolymer, P8, displayed broad-spectrum antimicrobial activity down to 0.5 μg/mL and retained strong activity after enzymatic degradation (minimum inhibitory concentration of 16 μg/mL). This superior performance arises from the rational design of the copolymer backbone and hydrophobic side chains. Notably, P8 demonstrated potent in vivo antibacterial performance and safety in mice models. These results highlight the design of functional self-similar polymers as a promising strategy to address bacterial resistance and meet the clinical demand for prolonged, low-toxicity antibacterial therapies.