A biomimetic nanoplatform for targeted co-delivery of ABT-199 and ATRA potentiates acute myeloid leukemia therapy via DNA damage response suppression.
TL;DR
HPAA is established as a promising biomimetic nanoplatform for AML therapy by integrating active targeting with the novel drug repurposing of ATRA as a Chk1 suppressor to potentiate ABT-199 efficacy.
Abstract
Despite its clinical utility, the therapeutic potential of Venetoclax (ABT-199) in acute myeloid leukemia (AML) remains limited by the heterogeneous nature of the disease, which often leads to reduced efficacy of monotherapy. Herein, we demonstrate that ABT-199-induced apoptosis can be potentiated by all-trans retinoic acid (ATRA) to suppress the DNA damage response. To address the lack of targeted drug delivery against AML and facilitate enhanced therapeutic efficacy, we engineered a biomimetic micelle, HPAA, by co-assembling an amphiphilic mPEG-ATRA conjugate with ABT-199 into micelles, followed by cloaking with P-selectin-rich membranes from activated human umbilical vein endothelial cells to target CD44 overexpressed on AML cells. The resulting HPAA micelles exhibited enhanced cellular uptake in MOLM13 cells, achieving approximately 2-fold higher uptake efficiency than non-targeted PAA micelles. Consequently, HPAA induced robust apoptosis and superior anti-leukemic effects, significantly suppressing MOLM13 cell proliferation in vitro. In an orthotopic AML model, HPAA preferentially accumulated in the bone marrow resident AML cells. Accordingly, treatment substantially reduced the MOLM13 cell burden in the peripheral blood, bone marrow and liver. This work establishes HPAA as a promising biomimetic nanoplatform for AML therapy by integrating active targeting with the novel drug repurposing of ATRA as a Chk1 suppressor to potentiate ABT-199 efficacy.