Lipid Nanoparticle Delivery of Small Proteins for Potent In Vivo RAS Inhibition

Mutated RAS proteins are potent oncogenic drivers and have long been considered “undruggable”. While RAS-targeting therapies have recently shown promise, there remains a clinical need for RAS inhibitors with more diverse targets. Small proteins represent a potential new therapeutic option, including...

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Bibliographic Details
Published in:ACS applied materials & interfaces 2023-05, Vol.15 (18), p.21877-21892
Main Authors: Haley, Rebecca M., Chan, Alexander, Billingsley, Margaret M., Gong, Ningqiang, Padilla, Marshall S., Kim, Emily H., Wang, Hejia, Yin, Dingzi, Wangensteen, Kirk J., Tsourkas, Andrew, Mitchell, Michael J.
Format: Article
Language:English
Subjects:
Animals
Biological and Medical Applications of Materials and Interfaces
cytosol
hepatoma
Lipids
Liposomes - metabolism
liver
Liver - metabolism
Mice
Nanoparticles
RNA, Small Interfering - metabolism
therapeutics
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Summary:Mutated RAS proteins are potent oncogenic drivers and have long been considered “undruggable”. While RAS-targeting therapies have recently shown promise, there remains a clinical need for RAS inhibitors with more diverse targets. Small proteins represent a potential new therapeutic option, including K27, a designed ankyrin repeat protein (DARPin) engineered to inhibit RAS. However, K27 functions intracellularly and is incapable of entering the cytosol on its own, currently limiting its utility. To overcome this barrier, we have engineered a lipid nanoparticle (LNP) platform for potent delivery of functional K27-D30a charge-modified version of the proteinintracellularly in vitro and in vivo. This system efficiently encapsulates charge-modified proteins, facilitates delivery in up to 90% of cells in vitro, and maintains potency after at least 45 days of storage. In vivo, these LNPs deliver K27-D30 to the cytosol of cancerous cells in the liver, inhibiting RAS-driven growth and ultimately reducing tumor load in an HTVI-induced mouse model of hepatocellular carcinoma. This work shows that K27 holds promise as a new cancer therapeutic when delivered using this LNP platform. Furthermore, this technology has the potential to broaden the use of LNPs to include new cargo typesbeyond RNAfor diverse therapeutic applications.
ISSN:1944-8244
1944-8252
1944-8252
DOI:10.1021/acsami.3c01501