自药物传递系统（DSDS）已广泛应用于增强药物负载能力和避免辅料相关的毒性问题。然而，不足的肿瘤靶向性，较差的肿瘤渗透性，突出的暴露释放和非特异性亚细胞分布仍然是主要障碍。在这里，我们报道了一种ROS敏感型两亲性前药（CPT-S-NO），通过硫醚键连接富脂亲水性庫铵-氧（TAO）基团和亲脂性喜树碱（CPT）合成，形成纳米颗粒型DSDS在水溶液中。与CPT-11和水溶性TAO修饰的CPT前药（CPT-NO）相比，CPT-S-NO表现出较长的血液循环时间，增强的肿瘤积累，深入的肿瘤穿透，高效的线粒体靶向和ROS激活的药物释放以诱导线粒体功能障碍，共同导致体内更优的抗肿瘤效果。这种TAO修饰策略为设计多效DSDS在各种药物中的潜在应用提供了希望。版权所有 © 2023，由Elsevier B.V.出版。

Drug self-delivery systems (DSDSs) have been extensively exploited to enhance drug loading capacity and avoid excipient-related toxicity issues. However, deficient tumor targeting, inferior tumor permeability, prominent burst release, and nonspecific subcellular distribution remain major obstacles. Herein, we reported a ROS-responsive amphiphilic prodrug (CPT-S-NO) synthesized by the conjugation of zwitterionic tertiary amine-oxide (TAO) moiety and hydrophobic camptothecin (CPT) through a thioether linkage, which formed a nanoparticulate DSDS in an aqueous solution. CPT-S-NO, compared with CPT-11 and the water-soluble TAO-modified CPT prodrug (CPT-NO), exhibited prolonged blood circulation, enhanced tumor accumulation, deep tumor penetration, efficient mitochondrial targeting, and ROS-activated drug release to induce mitochondrial dysfunction, corporately conducing to the superior antitumor efficacy in vivo. This TAO decoration strategy promises potential applications in designing multipotent DSDSs for various drugs.Copyright © 2023. Published by Elsevier B.V.