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

Abstract

ABSTRACT 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.