Co-delivery of siBcl-2 and PTX with mitochondria-targeted functions to overcoming multidrug resistance

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 HFnsiBcl-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 dualtargeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer.