MCL1 Inhibitor Augmented the Anti‐Glioma Efficacy of Paclitaxel Utilizing a Multifunctional Cascade Nanodrug System

Abstract Despite the importance of chemotherapy as a treatment option for glioma, its efficacy is often compromised by the formidable blood‐brain barrier (BBB) and drug resistance. To address these challenges, a novel cascade nanodrug system called A12‐PTX@RF‐NPs is designed with aims to penetrate the BBB and precisely target glioma. In this nanosystem, the RVG‐29 peptide facilitates the BBB penetration while Folic Acid (FA) targets glioma cells through binding to Folate Receptors (FR), followed by receptor‐mediated endocytosis subsequently. The incorporation of disulfide bond modifications enables responsive release within the reductive environment of glioma, ensuring successful delivery of chemotherapy drugs. Significantly, a co‐treatment approach involving the combination of A12 and PTX is implemented. In vitro and in vivo investigations have provided evidence that this amalgamation effectively induces apoptosis in tumor cells and inhibits their proliferation, thus synergistically eliminating both typical and drug‐resistant glioma cells. These findings suggest that the nanodrug system presents a promising therapeutic strategy for glioma treatment, surpassing the limitations of conventional chemotherapy. Specifically, A12‐PTX@RF‐NPs constructed in this research have demonstrated remarkable targeting capabilities and therapeutic effects in cellular as well as animal models, thereby proposing an innovative strategy for glioma treatment.