Switchable supramolecular polycationic assemblies for tunable antibacterial strategies against antibiotic resistance

Bacterial resistance significantly hampers the efficacy of antibiotics in eradicating pathogens and treating infections. Here, we introduce an Adaptive Cationic Therapeutic Integrated (ACTI) system, a design strategy integrating pyridinium cationic membrane disruption and tunable antibacterial activity to address this challenge. ACTI leverages the assembled hyper-enriched cationic domains to enhance the destruction of bacterial membranes, while also enabling the on-demand deactivation of antibacterial activity through disassembly, thereby safeguarding biocompatibility. Additionally, ACTI facilitates the photodynamic inactivation of negatively charged photosensitizers (TPPS) by promoting the interaction between the photosensitizer and bacteria as well as aiding the transport of singlet oxygen. ACTI-loaded photosensitizers (TPPS@ACTI) exhibited potent antibacterial activity (>99% pathogen elimination) against methicillin-resistant <i>S. aureus</i> (MRSA) and <i>E. coli in vitro</i>, and the antibacterial efficacy was further validated using an MRSA-infected murine wound model. ACTI establishes a paradigm shift for the design of tunable antimicrobials that balance potency and biosafety in complex biological environments.