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  • Organ- and Cell-Selective Delivery of mRNA In Vivo Using Guanidinylated Serinol Charge-Altering Releasable Transporters. Journal of the American Chemical Society Li, Z., Amaya, L., Ee, A., Wang, S. K., Ranjan, A., Waymouth, R. M., Chang, H. Y., Wender, P. A. 2024

    Abstract

    Selective RNA delivery is required for the broad implementation of RNA clinical applications, including prophylactic and therapeutic vaccinations, immunotherapies for cancer, and genome editing. Current polyanion delivery relies heavily on cationic amines, while cationic guanidinium systems have received limited attention due in part to their strong polyanion association, which impedes intracellular polyanion release. Here, we disclose a general solution to this problem in which cationic guanidinium groups are used to form stable RNA complexes upon formulation but at physiological pH undergo a novel charge-neutralization process, resulting in RNA release. This new delivery system consists of guanidinylated serinol moieties incorporated into a charge-altering releasable transporter (GSer-CARTs). Significantly, systematic variations in structure and formulation resulted in GSer-CARTs that exhibit highly selective mRNA delivery to the lung (97%) and spleen (98%) without targeting ligands. Illustrative of their breadth and translational potential, GSer-CARTs deliver circRNA, providing the basis for a cancer vaccination strategy, which in a murine model resulted in antigen-specific immune responses and effective suppression of established tumors.

    View details for DOI 10.1021/jacs.4c02704

    View details for PubMedID 38743019

  • Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism. Nature communications Li, Z., Amaya, L., Pi, R., Wang, S. K., Ranjan, A., Waymouth, R. M., Blish, C. A., Chang, H. Y., Wender, P. A. 2023; 14 (1): 6983

    Abstract

    The introduction of more effective and selective mRNA delivery systems is required for the advancement of many emerging biomedical technologies including the development of prophylactic and therapeutic vaccines, immunotherapies for cancer and strategies for genome editing. While polymers and oligomers have served as promising mRNA delivery systems, their efficacy in hard-to-transfect cells such as primary T lymphocytes is often limited as is their cell and organ tropism. To address these problems, considerable attention has been placed on structural screening of various lipid and cation components of mRNA delivery systems. Here, we disclose a class of charge-altering releasable transporters (CARTs) that differ from previous CARTs based on their beta-amido carbonate backbone (bAC) and side chain spacing. These bAC-CARTs exhibit enhanced mRNA transfection in primary T lymphocytes in vitro and enhanced protein expression in vivo with highly selective spleen tropism, supporting their broader therapeutic use as effective polyanionic delivery systems.

    View details for DOI 10.1038/s41467-023-42672-x

    View details for PubMedID 37914693

  • Circular RNA vaccine induces potent T cell responses. Proceedings of the National Academy of Sciences of the United States of America Amaya, L., Grigoryan, L., Li, Z., Lee, A., Wender, P. A., Pulendran, B., Chang, H. Y. 2023; 120 (20): e2302191120

    Abstract

    Circular RNAs (circRNAs) are a class of RNAs commonly found across eukaryotes and viruses, characterized by their resistance to exonuclease-mediated degradation. Their superior stability compared to linear RNAs, combined with previous work showing that engineered circRNAs serve as efficient protein translation templates, make circRNA a promising candidate for RNA medicine. Here, we systematically examine the adjuvant activity, route of administration, and antigen-specific immunity of circRNA vaccination in mice. Potent circRNA adjuvant activity is associated with RNA uptake and activation of myeloid cells in the draining lymph nodes and transient cytokine release. Immunization of mice with engineered circRNA encoding a protein antigen delivered by a charge-altering releasable transporter induced innate activation of dendritic cells, robust antigen-specific CD8 T cell responses in lymph nodes and tissues, and strong antitumor efficacy as a therapeutic cancer vaccine. These results highlight the potential utility of circRNA vaccines for stimulating potent innate and T cell responses in tissues.

    View details for DOI 10.1073/pnas.2302191120

    View details for PubMedID 37155869

  • Author Correction: Engineering circular RNA for enhanced protein production. Nature biotechnology Chen, R., Wang, S. K., Belk, J. A., Amaya, L., Li, Z., Cardenas, A., Abe, B. T., Chen, C., Wender, P. A., Chang, H. Y. 2022

    View details for DOI 10.1038/s41587-022-01472-2

    View details for PubMedID 35978134

  • Engineering circular RNA for enhanced protein production. Nature biotechnology Chen, R., Wang, S. K., Belk, J. A., Amaya, L., Li, Z., Cardenas, A., Abe, B. T., Chen, C., Wender, P. A., Chang, H. Y. 2022

    Abstract

    Circular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the promise of circRNA as a platform for gene expression. In this study, we developed a systematic approach for rapid assembly and testing of features that affect protein production from synthetic circRNAs. To maximize circRNA translation, we optimized five elements: vector topology, 5' and 3' untranslated regions, internal ribosome entry sites and synthetic aptamers recruiting translation initiation machinery. Together, these design principles improve circRNA protein yields by several hundred-fold, provide increased translation over messenger RNA in vitro, provide more durable translation in vivo and are generalizable across multiple transgenes.

    View details for DOI 10.1038/s41587-022-01393-0

    View details for PubMedID 35851375