Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon‐centered free radicals (R∙) can inactivate NF‐κB transcription by capping the active sites in both NF‐κB and DNA. We construct a type of thermosensitive R∙ initiator loaded amphiphilic nano‐micelles to facilitate intracellular delivery of R∙. At a temperature of 43°C, the generated R∙ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF‐κB through radical chain reaction. As a result, both NF‐κB nuclear translocation and NF‐κB‐DNA binding are suppressed, leading to a remarkable NF‐κB inhibition of up to 94.1%. We have further applied R∙ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF‐κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat‐sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

中文翻译：

---

碳自由基 (R∙) 灭活 NF-κB，用于自由基封端疗法

灭活过度激活的转录因子可以克服肿瘤治疗耐药性，但其不可成药的特性限制了常规抑制剂的开发。在这里，我们报道以碳为中心的自由基 (R∙) 可以通过封盖 NF-κB 和 DNA 中的活性位点来灭活 NF-κB 转录。我们构建了一种热敏 R∙ 引发剂负载的两亲性纳米胶束，以促进 R∙ 的细胞内递送。在 43°C 的温度下，生成的 R∙ 对核苷酸碱基中的双键进行亲电自由基加成，同时通过自由基链反应对 NF-κB 中的巯基残基进行加帽。结果，NF-κB 核转位和 NF-κB-DNA 结合均受到抑制，导致 NF-κB 抑制率高达 94.1%。我们进一步将 R∙ 胶束应用于临床射频消融肿瘤治疗模型，显示出显着的 NF-κB 失活，从而抑制肿瘤转移。激进封端策略不仅为解决临床肿瘤热疗中的散热效应提供了一种方法，也为癌症治疗中生物大分子的可控修饰提供了新的视角。