A Bimetallic Metal-Organic Framework-Based Biomimetic Nanoplatform Enhances Anti-Leukemia Immunity Via Synchronizing DNA Demethylation and RNA Hypermethylation.

Despite considerable progress achieved by immunotherapy against acute myeloid leukemia (AML) over the past decades, most patients relapse within 6 months. Epigenetic alterations-mediated antigenicity reducing in leukemic blasts (LBs) is one of the critical mechanisms of immune escape and resistance to T cell-based immunotherapy. Herein, we fabricated a bimetallic Mn 2+ /Fe 3+ metal-organic framework (MOF)-based biomimetic nanoplatform (termed as AFMMB) that consists of DNA hypomethylating agent, leukemia stem cells (LSCs) membrane and pro-autophagic Beclin-1 peptide. These AFMMB particles selectively targeted not only LBs but also LSCs due to the homing effect and immune compatibility of the LSC membrane, and induced autophagy by binding to the Golgi apparatus-associated protein. The autophagy-triggered dissolution of AFMMB released active components, resulting in the restoration of the stimulator of interferon genes (STING) pathway by inhibiting DNA methylation, upregulation of MHC-I molecules, and induction of RNA methylation-mediated decay of PD-L1 transcripts. These dual epigenetic changes eventually enhance T cell-mediated immune response due to increased antigenicity of AML cells. AFMMB also could suppress growth and metastases of solid tumor, which was suggestive of a pan-cancer effect. These findings demonstrated that AFMMB may serve as a promising new nanoplatform for dual epigenetic therapy against cancer and warrants clinical validation. This article is protected by copyright. All rights reserved.