Intracellular Dynamic Supramolecular Polymerization to Elicit Tumor Pyroptosis

Dynamic construction of macrostructures within living systems via supramolecular polymerization holds great potential for directing cellular fates. Current systems, however, are predominantly irreversible and often employ peptide- or nucleic-acid-based monomers vulnerable to enzymatic degradation. Herein, we present a dynamic supramolecular polymerization based on poly(SdG-<i>co</i>-PEG-MA), a copolymer featuring enzymatically stable deoxyguanosine (dG) and flexible poly(ethylene glycol) (PEG) pendants. In water, the dG pendants formed Hoogsteen-paired G-tetramers, yet their stacking was limited, yielding only truncated G-quadruplexes. The PEG pendants extended the assembly into three dimensions by bridging adjacent G-quadruplex units via hydrogen bonds with their deoxyribose moieties, leading to the formation of nanocubes, which we termed the dG-macromer. Upon exposure to high K⁺ levels (e.g., 100-150 mM in tumor cells), K⁺ ions were significantly included between dG-tetramers, and they mitigated the dipole-dipole repulsion between the carbonyl dipoles of the O6 atoms from adjacent tetrads, thereby initiating longitudinal supramolecular polymerization of the dG-macromer into "beads-on-a-string" fibers, and finally cross-linked nets. Crucially, this polymerization process was dynamic but noncyclic: K⁺ chelation by 18-crown-6 ether depolymerized the structures into small fragments, and the subsequent readdition of K⁺ failed to induce repolymerization. Intravenously administered dG-macromer remained inert in the bloodstream with a low K⁺ level, demonstrating a cubic morphology along with PEG-mediated prolonged systemic circulation and consequently enhanced tumor accumulation. Following cellular internalization and supramolecular polymerization, intracellular K⁺ was significantly depleted, which activated the Gasdermin D-mediated pyroptosis pathway, triggering immunogenic cell death marked by the release of damage-associated molecular patterns. Synergy with anti-PD-L1 amplified CD8⁺ T cell infiltration and effector function, demonstrating an augmented antitumor efficacy. This work presents a dynamic but noncyclic supramolecular polymerization system in response to a stepwise increase in K⁺ levels and expands the chemical toolkit for modulating cell fate.