Hypoxia-Initiated Supramolecular Free Radicals Induce Intracellular Polymerization for Precision Tumor Therapy

作者：Mian Tang, Zhiqing Yang, Xingchen Tang, He Ma, Beibei Xie, Jiang‐Fei Xu, Gao Cheng, David Bardelang, Ruibing Wang · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.4c14847 · 被引用次数：31 · 研究领域：Nanoplatforms for cancer theranostics、Supramolecular Chemistry and Complexes、Luminescence and Fluorescent Materials

Despite the development of various controlled release systems for antitumor therapies, off-target side effects remain a persistent challenge. In situ therapeutic synthesis from biocompatible substances offers a safer and more precise alternative. This study presents a hypoxia-initiated supramolecular free radical system capable of inducing intracellular polymerization, thereby disrupting the cytoskeleton and organelles within 4T1 cells. The system utilizes a 2:1 supramolecular host-guest complex of cucurbit[7]uril (CB[7]) and perylene diimide derivative (PDI), termed PDI+2CB[7], which is selectively reduced by the tumor's hypoxic and reducing environment to generate delocalized free radical anions. CB[7] effectively stabilizes these anions, enabling the PDI+2CB[7] complex to initiate free radical polymerization with 2-hydroxyethyl methacrylate (HEMA) inside the 4T1 cells. The resulting in situ polymerization significantly disrupts tumor metabolism, leading to a strong antitumor response without systemic toxicity. This study demonstrates that stable, endogenous stimulus-induced supramolecular free radicals can trigger intracellular polymerization reactions, achieving a selective and effective antitumor therapy without conventional chemotherapeutic agents.