Dual-mode action of scalable, high-quality engineered stem cell-derived SIRP alpha extracellular vesicles for treating acute liver failure

Kim, S.; Kim, Y. K.; Choi, Y.-S.; Lee, I.; Joo, H.; Kim, J.; Kwon, M.; Park, S.; Jo, M. K.; Choi, Y.; D'Souza, T.; Jung, J. W.; Zakhem, E.; Lenzini, S.; Woo, J.; Choi, H.; Park, J.; Park, S.-Y.; Kim, G. B.; Nam, G.-H.; Kim, I.-S.

doi:10.1101/2024.05.24.592430

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bioRxiv · 10.1101/2024.05.24.592430

Dual-mode action of scalable, high-quality engineered stem cell-derived SIRP alpha extracellular vesicles for treating acute liver failure

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Abstract

Acute liver failure (ALF) is a critical inflammatory condition characterized by rapid hepatocyte death, impaired liver regeneration due to the delayed removal of necroptotic cells, and high mortality rates. This study introduces a novel dual-mode action therapeutic approach using extracellular vesicles expressing Signal Regulatory Protein Alpha (SIRP-EVs) derived from genetically engineered mesenchymal stem cells (MSCs). These SIRP-EVs are designed to concurrently resolve necroptosis and promote liver regeneration. Our studies identified CD47 and SIRP as promising therapeutic targets for ALF. We developed a scalable 3D bioreactor-based process that produces high-purity SIRP-EVs, which preserve MSC properties and achieve significant production levels. SIRP-EVs target both macrophages and necroptotic hepatocytes in ALF models, enhancing macrophage phagocytic activity against necroptotic cells via CD47 blockade and promoting liver regeneration by reprogramming macrophages with MSC-derived cargo. Comprehensive in vitro and in vivo studies demonstrate that SIRP-EVs decrease CD47+ necroptotic cells and promote liver regeneration in ALF models, leading to reduced liver damage markers and enhanced survival rates. These findings highlight the potential of SIRP-EVs as a dual-mode action therapeutic for ALF, offering promising prospects for their application in other inflammatory diseases. Moreover, these results pave the way for advancing engineered EV-based therapies toward clinical implementation.

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Kim, S., Kim, Y. K., Choi, Y.-S., Lee, I., Joo, H., Kim, J., Kwon, M., Park, S., Jo, M. K., Choi, Y., D'Souza, T., Jung, J. W., Zakhem, E., Lenzini, S., Woo, J., Choi, H., Park, J., Park, S.-Y., Kim, G. B., Nam, G.-H., Kim, I.-S.. 2024-05-29. Dual-mode action of scalable, high-quality engineered stem cell-derived SIRP alpha extracellular vesicles for treating acute liver failure. https://doi.org/10.1101/2024.05.24.592430

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