Haabeth, O. | Search bioRxiv

bioRxiv2025

In vivo mRNA delivery to the lung vascular endothelium by dicationic Charge-Altering Releasable Transporters

Endothelial cells (EC) comprise the pulmonary vascular bed and play a significant role in health and disease. Consequently, the EC niche represents an attractive therapeutic target for treating a wide range of pulmonary vascular diseases. We have identified a new class of dicationic Charge-Altering Releasable Transporters. These single-component transporters selectively deliver mRNA to the lung upon intravenous administration without the use of a targeting ligand. Significantly, the number and spatial array of cationic charges within the repeating units of the CART polymer are found to control both mRNA delivery efficacy and tissue tropism. High-resolution imaging revealed efficient mRNA delivery to endothelial cells in pulmonary arteries, veins and capillaries. The selective lung tropism of these new CARTs, coupled with the efficient and tunable synthesis of this new family of CART amphiphiles, represents an enabling platform for research and clinical applications.

bioengineering↗

bioRxiv2021

An mRNA SARS-CoV-2 vaccine employing a novel delivery vehicle with a TLR-9 agonist induces neutralizing antibodies and T cell memory

The SARS-CoV-2 pandemic has necessitated the rapid development of prophylactic vaccines. Two mRNA vaccines have been approved for emergency use by the FDA and have demonstrated extraordinary effectiveness. The success of these mRNA vaccines establishes the speed of development and therapeutic potential of mRNA. These authorized vaccines encode full-length versions of the SARS-CoV-2 spike protein. They are formulated with Lipid Nanoparticle (LNP) delivery vehicles that have inherent immunostimulatory properties. Different vaccination strategies and alternative mRNA delivery vehicles would be desirable to ensure flexibility of future generations of SARS-CoV-2 vaccines and the development of mRNA vaccines in general. Here, we report on the development of an alternative mRNA vaccine approach using a delivery vehicle called Charge-Altering Releasable Transporters (CARTs). Using these inherently nonimmunogenic vehicles we can tailor the vaccine immunogenicity by inclusion of co-formulated adjuvants such as oligodeoxynucleotides with CpG motifs (CpG-ODN). Mice vaccinated with the mRNA-CART vaccine developed therapeutically relevant levels of RBD-specific neutralizing antibodies in both the circulation and in the lung bronchial fluids. In addition, vaccination elicited strong and long lasting RBD-specific TH1 T cell responses including CD4+ and CD8+ T cell memory.

immunology↗