Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid‐functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π–π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro‐apoptotic reactions by promoting the dissociation of the pro‐apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor‐loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H₂O₂‐triggered drug release, and significant cytotoxicity toward MOLM‐13‐Luc and MV‐411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL⁻¹, respectively. In mice bearing MOLM‐13‐Luc or MV‐411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid‐functionalized smart nanodrugs hold remarkable potential for AML treatment.