<i>In Vivo</i> mRNA Delivery to the Lung Vascular Endothelium by Dicationic Charge-Altering Releasable Transporters
Endothelial cells (ECs) comprise the pulmonary vascular bed and play a significant role in health and diseases. 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.
Authors
- Jeffrey Ni (ORCID: https://orcid.org/0000-0002-3457-8447)
- Idit Sagiv-Barfi (ORCID: https://orcid.org/0000-0002-8372-9096)
- Robert M. Waymouth (ORCID: https://orcid.org/0000-0001-9862-9509)
- Ole Audun Werner Haabeth (ORCID: https://orcid.org/0000-0002-1153-9250)
- Salwa Masud (ORCID: https://orcid.org/0000-0003-2931-7418)
- Rebecca L. McClellan
- Marco Herrera‐Barrera (ORCID: https://orcid.org/0000-0001-7593-907X)
- Paul A. Wender (ORCID: https://orcid.org/0000-0001-6319-2829)
- Adrienne Sallets (ORCID: https://orcid.org/0000-0002-3333-7609)
- Summer Ramsay-Burrough (ORCID: https://orcid.org/0000-0002-0575-4835)
- Maya E. Kumar (ORCID: https://orcid.org/0000-0001-6754-5660)
- Ronald Levy (ORCID: https://orcid.org/0000-0003-2061-0650)
- Paul J. Hurst (ORCID: https://orcid.org/0000-0002-1826-2549)
- Timothy R. Blake (ORCID: https://orcid.org/0000-0001-7548-1492)
- Yuan Jia (ORCID: https://orcid.org/0000-0002-7928-3917)
- Debra K. Czerwinski
- Mahmoud M. AbdElwakil (ORCID: https://orcid.org/0000-0002-2450-6669)
- Samuel R. Khasnavis
Institutions
- Cancer Institute (WIA) (IN)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Regenerative Medicine Institute (MX)
- Pulmonary Associates (US)
- Stanford University (US)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1021/jacs.5c06654
- Citations
- 2
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 1.61