多药耐药性（MDR）对临床环境中化疗的功效构成了重大障碍。尽管紫杉醇（PTX）被指定为治疗复发性和转移性乳腺癌的主要药物，但PTX耐药的出现经常导致治疗缺陷，成为临床乳腺癌治疗的重大障碍。作为回应，我们开发了一种对肿瘤和线粒体表现出双重特异性的递送系统。该系统促进了小干扰B细胞淋巴瘤-2（siBcl-2）和PTX分别顺序给药至肿瘤细胞质和线粒体，目的是通过激活线粒体凋亡途径来克服肿瘤细胞中的PTX耐药性。值得注意的是，我们采用基因工程技术来制造含有 H 亚基 (HFn) 的重组铁蛋白，该亚基以其肿瘤靶向能力而闻名，用于负载 siBcl-2。然后将该 HFn-siBcl-2 复合物与带正电荷的三苯膦-脂质体@PTX (TL@PTX) 纳米粒子 (NP) 组合，形成 HFn/siBcl-2@TL/PTX。在HFn的引导下，这些纳米粒子有效地进入细胞，并通过三苯膦（TPP）介导的“质子海绵”的作用释放siBcl-2，从而精确调节Bcl-2蛋白的表达。同时，PTX通过TL@PTX的精准靶向定向至线粒体，协同启动线粒体凋亡途径，有效抑制体外和体内的PTX耐药。总之，这种双靶向递送系统的开发为乳腺癌临床治疗中克服 PTX 耐药性提供了一种有前途的治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Multidrug resistance (MDR) poses a significant impediment to the efficacy of chemotherapy in clinical settings. Despite Paclitaxel (PTX) being designated as the primary pharmaceutical agent for treating recurrent and metastatic breast cancer, the emergence of PTX resistance frequently results in therapeutic shortcomings, representing a substantial obstacle in clinical breast cancer management. In response, we developed a delivery system exhibiting dual specificity for both tumors and mitochondria. This system facilitated the sequential administration of small interfering B-cell lymphoma-2 (siBcl-2) and PTX to the tumor cytoplasm and mitochondria, respectively, with the aim of surmounting PTX resistance in tumor cells through the activation of the mitochondrial apoptosis pathway. Notably, we employed genetic engineering techniques to fabricate a recombinant ferritin containing the H-subunit (HFn), known for its tumor-targeting capabilities, for loading siBcl-2. This HFn-siBcl-2 complex was then combined with positively charged Triphenylphosphine-Liposome@PTX (TL@PTX) nanoparticles (NPs) to formulate HFn/siBcl-2@TL/PTX. Guided by HFn, these nanoparticles efficiently entered cells and released siBcl-2 through the action of triphenylphosphine (TPP)-mediated "proton sponge," thereby precisely modulating the expression of Bcl-2 protein. Simultaneously, PTX was directed to the mitochondria through the accurate targeting of TL@PTX, synergistically initiating the mitochondrial apoptosis pathway and effectively suppressing PTX resistance both in vitro and in vivo. In conclusion, the development of this dual-targeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer.Copyright © 2024. Published by Elsevier B.V.