纳米医学在靶向癌症化疗方面具有潜在的用途；然而，设计具有可控结构和功能的纳米医学以克服一系列生物和病理屏障以有效杀灭体内癌细胞是很困难的。在这里，我们报告了从白蛋白中原位生长双酸敏感的聚（三级胺）-阿霉素共轭物，形成了双酸敏感的白蛋白-聚（三级胺）-阿霉素共轭物，这些共轭物以受控方式自组装成纳米球和纳米蠕虫。纳米球和纳米蠕虫在pH<6.9时迅速解离成带正电的单体，并在pH<5.6时迅速释放了阿霉素共轭药物，从而提高了在肿瘤细胞团块中的穿透性以及在pH<6.9时对肿瘤细胞的摄取和细胞毒性。值得注意的是，纳米蠕虫比纳米球和阿霉素被内皮细胞吸收较少，这导致了改善的药物动力学效应。在三阴性乳腺癌小鼠模型中，与纳米球和阿霉素相比，纳米蠕虫更高效地积聚和穿透肿瘤，从而提高了肿瘤的积聚和穿透。因此，纳米蠕虫在抑制肿瘤生长和延长动物存活时间方面优于纳米球和阿霉素，并且未观察到副作用。这些发现表明，具有空间时间可编程的双酸敏感特性的智能纳米蠕虫是有前景的下一代靶向癌症化疗纳米医学。该文章受版权保护。保留所有权利。

Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to overcome a series of biological and pathological barriers to efficiently kill cancer cells in vivo. Here, we report in situ growth of dual-acid-sensitive poly(tertiary amine)-doxorubicin conjugates from albumin to form dual-acid-sensitive albumin-poly(tertiary amine)-doxorubicin conjugates that self-assemble into nanospheres and nanoworms in a controlled manner. Both nanospheres and nanoworms rapidly dissociated into positively-charged unimers at pH < 6.9 and quickly released the conjugated drug of doxorubicin at pH < 5.6, leading to enhanced penetration in tumor cell spheroids as well as improved uptake and cytotoxicity to tumor cells at pH < 6.9. Notably, nanoworms were less taken up by endothelial cells than nanospheres and doxorubicin, leading to improved pharmacokinetics. In a mouse model of triple negative breast cancer, nanoworms accumulated and penetrated into tumors more efficiently than nanospheres and doxorubicin, leading to enhanced tumor accumulation and penetration. As a result, nanoworms outperformed nanospheres and doxorubicin in suppressing tumor growth and elongating the animal survival time, without observed side effects. These findings demonstrate that intelligent nanoworms with spatiotemporally programmed dual-acid-sensitive properties are promising as next-generation nanomedicines for targeted cancer chemotherapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.