Stimuli-Responsive “Arm-First” Star Copolymers for Antibacterial Activity and Biocompatibility

The escalating threat of antimicrobial resistance requires innovative therapeutic strategies. Host-defense peptides and their synthetic mimics show promise but face limitations due to cytotoxicity from nonspecific mammalian cell interactions. Here, we synthesized 12 amphiphilic cationic polymers with linear (LPs) and star (SPs) topologies, incorporating hydrophobic monomer ratios of 10–30%. LPs were prepared by RAFT polymerization and subsequently converted into core-cross-linked SPs, either degradable or non-degradable, via an arm-first strategy with three different cross-linkers. Antibacterial assays demonstrated that LPs exhibited superior activity compared with SPs. Notably, our copolymers showed potent efficacy against multidrug-resistant Pseudomonas aeruginosa (PA 37), disrupting bacterial membranes more efficiently than colistin and eradicating E. coli within 15 min. SPs, however, displayed enhanced hemocompatibility and an improved safety profile marked by high selectivity. Incorporation of disulfide bonds in SP cores imparted stimuli-responsive degradation, enhancing their potential as transient delivery systems. These findings highlight the potential of rational polymer design for safe, effective, and biodegradable antibacterial agents.