Dynamic Supramolecular Probe With Chloride‐Guided Assembly and DNA‐Mediated Intracellular Reorganization for Tumor Therapy

Subcellularly targeted molecules usually act through static localization, whereas systems that undergo environment-triggered state transitions and functional reprogramming remain underexplored. Here, we develop alkyl-chain-tunable Ly-Cn molecules whose intracellular behavior is governed by chloride-dependent assembly and DNA-mediated supramolecular reorganization. Responsiveness varies nonmonotonically with chain length, with Ly-12 achieving an optimal balance. At physiologically relevant chloride concentrations, Ly-12 undergoes a threshold-like aggregation transition into supramolecular nanoparticles that are subsequently reorganized and disassembled by DNA. This dual-responsive process drives initial accumulation in lysosome-associated compartments, followed by lysosome-to-nucleus redistribution and DNA-mediated nuclear trapping. Ly-12 thereby acts beyond passive nuclear targeting: it initiates lysosomal perturbation that propagates into oxidative stress, endoplasmic-reticulum stress, and DNA damage, while white-light irradiation amplifies this cascade. Transcriptomic analysis corroborates the progressive stress response. In HeLa xenografts, intratumoral Ly-12 produces marked antitumor efficacy that is further enhanced by white-light irradiation, without evident systemic toxicity. These findings establish an environment-responsive supramolecular strategy that converts ion-regulated assembly and organelle redistribution into light-amplified therapeutic activity.