Abstract
We report a silver-based metallosupramolecular polymer system designed for multifunctional therapeutic applications, in which metal-organic coordination motifs integrated into a hydrophilic oligomer enable spontaneous self-assembly into stable nanostructures that exert broad-spectrum antibacterial activity, selective anticancer efficacy, and potent antiviral performance. We hypothesized that cytosine-silver-cytosine (Cy-Ag-Cy) coordination could regulate polymer association and nanoscale self-assembly, thereby coupling molecular organization with the colloidal and stimulus-responsive properties of the resulting nanogels. Herein, we construct a water-soluble supramolecular polymer (Ag-CyPEG) featuring cytosine-silver-cytosine coordination units, which self-assemble in aqueous media into nanogels that exhibit strong intrinsic fluorescence, pronounced pH responsiveness, high stability in biological environments, and excellent anti-hemolytic behavior, indicating suitability for biomedical applications. Biofunctionally, Ag-CyPEG nanogels exhibited excellent antibacterial activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, achieving efficient cell killing with rapid kinetics. The nanogels also showed strong anticancer selectivity, as they induced substantial apoptosis across multiple cancer cell lines but exerted negligible toxicity toward normal cells, attributed to selective cellular internalization and acid-triggered disassembly within cancer cells. Importantly, the nanogels also suppressed H1N1 influenza A viral activity prior to cellular entry and prevented viral propagation, indicating their ability to suppress infection. Collectively, these findings establish a coordination-driven nanogel platform in which molecular Cy-Ag-Cy interactions are translated into nanoscale self-assembly, colloidal properties, and stimulus-responsive behavior, providing a conceptual framework for the design of multifunctional metallosupramolecular materials with integrated biological functions. SIGNIFICANCE OF THE STUDY: This study establishes a generalizable metallosupramolecular design strategy that unifies intrinsic fluorescence and broad-spectrum bioactivity within a single silver-cytosine coordination-driven nanoplatform. Beyond integrating antibacterial, anticancer, and antiviral activities, this system defines a mechanistic framework in which microenvironment-responsive metal-ligand interactions enable selective activation of silver ion-mediated therapeutic action. This strategy shifts nanomedicine design from static, single-function systems toward adaptive, coordination-programmed platforms with context-dependent bioresponsiveness. Importantly, this provides a transferable blueprint for engineering multifunctional supramolecular therapeutics with tunable activity, high biocompatibility, and minimized systemic toxicity. More broadly, this work establishes a new paradigm for precision nanomedicine, in which structural programming at the supramolecular level enables rational development of intelligent, multi-target therapeutic systems with broad translational impact.