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

Abstract

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.

Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine

“…22 Recently, the composition of biomolecular coronas was also found to regulate fate and/or utility of LNPs. 28,29 In our previous studies we found that the enrichment of immunoglobulins and complement proteins in biomolecular coronas is correlated with donor-specific nanoparticle association with human blood immune cells. 19 The studies herein demonstrate that anti-PEG antibodies are key immunoglobulins that drive the donor-dependent immune cell association of PEG-containing nanoparticles in human blood.…”

Quality by Design for enabling RNA platform production processes

“…Among others, while neutral particle surface is desired in current RNA vaccine, surface charge appears to be a crucial parameter in organ targeting and in determining lymph node-and mucus-penetrating ability [47][48][49]. In addition, the LNP molecular composition and size both play an evident role in product biodistribution and activity [50][51][52].…”

In vivo fate and intracellular trafficking of vaccine delivery systems

“…Recent work showed that the behavior of nanoparticles in the body can differ significantly depending on the protein(s) attached to the nanoparticle surface [78] . The types of serum proteins that adhere to the surface vary by the surface charge of the lipid nanoparticle.…”