Charge-Programmable Alternating Copolymers via Self-Catalyzed Aqueous Polymerization for Tunable Bacterial Translocation and Macrophage Polarization.

Precise control over sequence and charge distribution is essential for emulating biological macromolecules yet remains synthetically challenging. Here, we introduce a self-catalyzed aqueous amine-epoxy polymerization using amino acid salts, transforming a classical cross-linking chemistry into a versatile route for sequence-defined, charge-programmable alternating copolymers. The salts generate an intrinsic alkaline microenvironment that prevents amine protonation and enables direct ionic incorporation with alternating sequence fidelity. Mechanistic studies reveal the kinetic dominance of deprotonated primary amines in chain propagation among competing aqueous nucleophiles. By orthogonally paring charge-defining amino acid salts and flexibility-tuning diepoxides, we constructed a 20-copolymer library covering cationic, zwitterionic, and anionic regimes. These polymers exhibit programmable biointerfacial behaviors: cationic sequences promote bacterial membrane anchoring, backbone flexibility governs translocation dynamics (seconds to minutes), and zwitterionic or anionic sequences induce M2 macrophage polarization without membrane disruption. This work establishes a unified platform connecting polymer sequence design to predictable bacterial translocation and immunomodulatory functions.