Cancer‐Selective Intracellular Polymerization via Acrolein‐Driven Cyclodimerization Cascade

Abstract The intracellular polymerization of synthetic macromolecules presents a unique method for modifying cell behavior, enabling real‐time imaging, and enhancing therapeutic effectiveness. However, most current strategies rely on external catalysts or non‐physiological triggers, often lacking target‐cell specificity. Here, we report a cancer‐selective intracellular cyclodimerization cascade polymerization driven solely by endogenous acrolein, an oncometabolite overproduced in malignant cells. Acrolein plays dual roles as a polymerization initiator through imine formation and as a structural component of the resulting polymer. We designed a meta ‐phenylene‐bis(2‐aminoethanol) monomer that incorporates an aggregation‐induced emission (AIE)‐active tetraphenylethylene unit. In acrolein‐rich cancer cells, condensation between the aminoethanol groups and acrolein generates imines, which then undergo a spontaneous, catalyst‐free cyclodimerization cascade, yielding eight‐membered 1,5‐diazacyclooctane polymers that embed native acrolein. This polymerization triggers robust AIE fluorescence “turn‐on”, facilitating high‐contrast imaging of malignant cells with minimal background in healthy cells. We demonstrated selective fluorescence in multiple cancer cell lines and applied this platform to freshly resected human breast tumor samples, showing its utility for rapid intraoperative assessment. This strategy establishes a versatile toolkit for precision diagnostics, engineered intracellular materials, and next‐generation therapeutics.