Lysosomal Membrane‐Biomimetic Metal‐Organic Framework Potentiates Autophagy/Epigenetic‐Mediated Anti‐Tumor Immunity

Abstract The loss of major histocompatibility complex I (MHC‐I) in leukemia cells limits their recognition by T cells, leading to leukemia relapse and resistance to immunotherapy. MHC‐I molecules are often degraded by an autophagy‐dependent mechanism and are still considered “undruggable”. Herein, a lysosomal membranes‐based biomimetic metal‐organic framework (MOF) nanoplatforms (PFMALM) is reported. PFMALM is developed by coating a histone deacetylase inhibitor‐loaded MIL‐53(Fe) with lysosomal and leukemia cell membranes derived from the primary tissue. PFMALM is selectively taken up by the leukemia cells following targeted delivery to the leukemia microenvironment on account of the homing affinity of the leukemia cell membrane. Most importantly, PFMALM can not only upregulate MHC‐I transcripts via hyperacetylating histone H3 but also increase surface MHC‐I expression by protecting the MHC‐I from autophagy‐dependent lysosomal degradation. In addition, PFMALM increased global m 6 A RNA modification, leading to the transcriptional repression of the programmed death ligand 1 (PD‐L1). The increase in surface MHC‐I and reduction in PD‐L1 synergistically enhanced the recognition and clearance of leukemic cells by the cytotoxic T cells. PFMALM also exhibited a broad anti‐tumor activity in mouse models of leukemia, multiple myeloma, and breast cancer. This study provides proof‐of‐concept of a lysosomal‐based biomimetic nanoplatform as a novel epigenetic drug for broad‐spectrum anti‐tumor immunity.