Multifunctional liposomal nanostructure-mediated siRNA/bortezomib co-delivery for SHARP1 knockdown in MLL-AF6 acute myeloid leukemia.

Sameh A Mohammed, Yang Ju

Biomaterials advances 2022 Mar

filter terms:

Acute myeloid leukemia (AML) has an extremely poor prognosis and high relapse and fatality rates. New therapeutic mechanisms for molecular targeted delivery are urgently needed to improve patient survival. In this study, we targeted the oncogenic transcription factor SHARP1 using multifunctional small interfering RNA (siRNA) and bortezomib (BTZ)-loaded cRGD-guided PEGylated cationic liposomal nanostructures to monitor their antileukemic activity in MLL-AF6 AML cells. Efficient siRNA/BTZ co-delivery by the nanostructures inhibited cell viability and the clonogenic growth as well as stimulated apoptosis of AML cells. We hypothesized that SHARP1 downregulation induced the accumulation of non-functional MLL-AF6, DOT1L, MEN1, and LEDGF fusion proteins, preventing MLL-AF complex formation and downregulating RAS-GTP and Bcl-2 expression, consequently triggering autophagy and apoptosis. The BTZ combination substantially augmented therapeutic synergy and enhanced autophagic and apoptotic events. Our findings demonstrate a state-of-the-art biodegradable nanoplatform for siRNA/BTZ co-delivery with targeted SHARP1 knockdown, demonstrating a potential therapeutic option for MLL-AF6 AML. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Sameh A Mohammed, Yang Ju. Multifunctional liposomal nanostructure-mediated siRNA/bortezomib co-delivery for SHARP1 knockdown in MLL-AF6 acute myeloid leukemia. Biomaterials advances. 2022 Mar;134:112663