On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles

By Sean A. Dilliard, Qiang Cheng, D. Siegwart. Proceedings of the National Academy of Sciences of the United States of America, 2021

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Significance Liver accumulation represents a significant barrier in the development of therapeutically efficacious nanoparticle drug delivery systems. Using a series of lipid nanoparticles with distinct organ-targeting properties, we provide evidence for a plausible mechanism of action for nanoparticle delivery to non-liver tissues. Following intravenous injection, specific proteins in the blood are recruited to the nanoparticle’s surface based on its molecular composition and they endow it with a unique biological identity that governs its ultimate fate in the body. An innovative paradigm emerges from this mechanistic understanding of nanoparticle delivery—endogenous targeting—wherein the molecular composition of a nanoparticle is rationally engineered to interact with specific proteins in the blood to overcome liver accumulation and to target specific organs. Lipid nanoparticles (LNPs) are a clinically mature technology for the delivery of genetic medicines but have limited therapeutic applications due to liver accumulation. Recently, our laboratory developed selective organ targeting (SORT) nanoparticles that expand the therapeutic applications of genetic medicines by enabling delivery of messenger RNA (mRNA) and gene editing systems to non-liver tissues. SORT nanoparticles include a supplemental SORT molecule whose chemical structure determines the LNP’s tissue-specific activity. To understand how SORT nanoparticles surpass the delivery barrier of liver hepatocyte accumulation, we studied the mechanistic factors which define their organ-targeting properties. We discovered that the chemical nature of the added SORT molecule controlled biodistribution, global/apparent pKa, and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surface-bound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle’s surface can enable drug delivery beyond the liver.

Subfields: Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b01283d625815003477c4c3961b7b256cee4ec2d