UiO-66 MOFs-Based "Epi-Nano-Sonosensitizer" for Ultrasound-Driven Cascade Immunotherapy against B-Cell Lymphoma.

in ACS nano by Zhihua Wang, Mingda Han, Yiqiao Wang, Ning Wang, Yilin Yang, Bingru Shao, Qiannan Miao, Zhan Shi, Fei Yan, Shouhua Feng

TLDR

  • Researchers developed a metal-organic framework-based nano-sonosensitizer that uses ultrasound-driven cascade immunotherapy to treat B-cell lymphoma by inducing immunogenic cell death and activating CD8+ T cells.

Abstract

B-cell lymphoma (BCL) is a hematological malignancy with high heterogeneity and represents an aggressive proliferation of mature B-cells. Despite the initial success of traditional treatments for BCL in clinical trials, a majority of patients eventually develop resistance to therapy and have poor clinical outcomes. Epigenetic dysregulation is a major contributor to the pathogenesis of BCL, and therapies targeting epigenetic pathways is a promising alternative strategy for treating BCL. Herein, we developed a metal-organic framework (MOF)-based nano-sonosensitizer for ultrasound-driven cascade immunotherapy against BCL. The nano-sonosensitizer was synthesized by encapsulating copper complex of the mA-mRNA demethylase inhibitor into UiO-66-NH, which possesses a Z-scheme heterostructure and allows efficient electron-hole pair separation for generating reactive oxygen species (ROS) under ultrasound activation. These CuR@UiO66 sonosensitizers were functionalized with mPEG-POand anti-CD19 antibody, and the resulting CRUPPA19 particles could specifically accumulate in the BCL tissue and also target lymphoma cells that infiltrated into the bone marrow. Once internalized, CRUPPA19 could induce intracellular ROS production and apoptosis under ultrasound irradiation. Subsequently, ultrasonic stimulation triggered autophagy-mediated release of Cu and Rhein from CRUPPA19, thereby increasing protein lipoylation and global mRNA methylation, which led to cuproptosis and the transcriptional repression PDL1, respectively. These cascades synergistically induced immunogenic cell death in the tumors and promoted activation of CD8T cells, eventually leading to an antilymphoma immune response. CRUPPA19-mediated sono-immunotherapy not only eliminated the primary and metastatic lymphomas but also cleared lymphoma cells from the bone marrow. This study provided an insight into a MOF-based nanoepigenetic therapy platform with ultrasound-triggered cascade amplification for enhanced antihematological tumor immunity.

Overview

  • The study focused on developing a metal-organic framework (MOF)-based nano-sonosensitizer for ultrasound-driven cascade immunotherapy against B-cell lymphoma (BCL).
  • The nano-sonosensitizer was designed to encapsulate a copper complex of an mA-mRNA demethylase inhibitor within a Z-scheme heterostructured MOF (UiO-66-NH) for efficient electron-hole pair separation and reactive oxygen species (ROS) generation under ultrasound activation.
  • The primary objective of the study was to explore the potential of MOF-based nanoepigenetic therapy as a novel approach for treating BCL, with a focus on the synergistic induction of immunogenic cell death and activation of CD8+ T cells through epigenetic modulation and ultrasonic stimulation.

Comparative Analysis & Findings

  • The study demonstrated that the CRUPPA19 particles could specifically accumulate in BCL tissue and target lymphoma cells that infiltrated into the bone marrow, inducing intracellular ROS production and apoptosis under ultrasound irradiation.
  • The ultrasonic stimulation triggered autophagy-mediated release of Cu and Rhein from CRUPPA19, leading to increased protein lipoylation and global mRNA methylation, which in turn induced cuproptosis and transcriptional repression of PDL1.
  • The CRUPPA19-mediated sono-immunotherapy resulted in the elimination of primary and metastatic lymphomas, as well as clearance of lymphoma cells from the bone marrow, suggesting a synergistic and effective treatment strategy for BCL.

Implications and Future Directions

  • The study highlighted the potential of MOF-based nanoepigenetic therapy as a promising alternative strategy for treating BCL, combining the advantages of ultrasound-driven gene therapy and immunotherapy.
  • Future studies could investigate the optimal design and fabrication of MOFs for enhanced therapeutic efficacy and reduced toxicity, as well as the exploration of additional epigenetic targets for synergistic treatment benefits.
  • The nanoepigenetic therapy platform developed in this study could be expanded to treat other hematological malignancies or solid tumors, and its potential for overcoming treatment resistance and improving patient outcomes warrants further investigation.
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