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

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 m⁶A-mRNA demethylase inhibitor into UiO-66-NH₂, 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-PO₃ and 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 CD8⁺ T 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.