Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody–drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.

放射治疗诱导的前药激活为降低癌症治疗中化疗的全身毒性提供了理想的解决方案，但放射激活的保护基团的范围有限。在这里，我们提出成熟的光诱导电子转移化学可能为开发多功能辐射可去除保护基团铺平道路。使用功能性报告基因检测，N-烷基-4-吡啶鎓 (NAP) 被鉴定为一种通过释放客户分子来有效响应辐射的笼蔽基团。在竞争实验中进行评估时，NAP 部分比迄今为止发现的其他可辐射去除的保护基团更有效。利用这一特性，我们开发了一种 NAP 衍生的氨基甲酸酯连接体，可在辐射下释放荧光团和毒素，并将其纳入抗体药物偶联物 (ADC) 中。这些设计的 ADC 在活细胞和荷瘤小鼠中具有活性，突显了使用这种可辐射去除的保护基团来开发具有更高稳定性和治疗效果的下一代 ADC 的潜力。