In recent years, as a new pharmaceutical technology, mRNA has made a breakthrough in the field of infectious diseases and tumor treatment in a short time. However, how to deliver mRNA drugs safely and efficiently to specific target cells and protect them from degradation is one of the main obstacles to mRNA therapy.

The ideal delivery carrier must be safe, stable, and organ-specific. Lipid nanoparticles (LNPs) are the most advanced mRNA delivery carriers in clinic. At present, all COVID-19 mRNA vaccines under development or approved for clinical use are delivered using LNP vectors. LNP provides many benefits for mRNA delivery, including simplicity, modularity, biocompatibility, and large mRNA payloads.

However, clinical studies have shown that LNPs accumulate in the liver, so most of the current LNP delivery systems are liver-targeted, and the effective delivery of non-hepatic organs such as lungs and kidneys needs to be solved.

Professor Daniel Siegwart of the University of Texas Southwestern Medical Center and Dr. Qiang Cheng, a co-author, published a research paper entitled On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles in the Proceedings of the National Academy of Sciences (PNAS).

The team previously developed a selective organ-targeting lipid nanoparticle and named it SORT (selective organ targeting), which can specifically target liver, lung, spleen, and other organs by adding new SORT lipids.

This study further analyzed the specific mechanism that this selective organ-targeted lipid nanoparticles can achieve tissue-specific delivery. This will greatly expand the scope of application of mRNA vaccines and drugs, as well as CRISPR gene editing therapy.

A lipid nanoparticle usually consist of four components, ionizable lipid, cholesterol, helper phospholipid, and polyethylene glycol lipid, which form a nanoparticle with mRNA in acidic buffers to encapsulate and protect fragile mRNA. In addition, they are positively charged in the acidic environment of the inclusion body, which promotes their fusion with the connotative body membrane and releases them into the cytoplasm.

Prior to the publication of the PNAS paper, Professor Daniel Siegwart’s team found that the addition of a fifth component, SORT lipid, to lipid nanoparticle could change the organ targeting properties of LNP in vivo and achieve mRNA delivery to organs outside the liver. More importantly, this SORT-LNP can be extended to a variety of extrahepatic organs and tissues to achieve mRNA delivery to lungs, kidneys, and even epithelial cells and immune cells. The study was published in the journal Nature Nanobitechnology in April 2020.

This paper has aroused widespread concern in the field of medicine since it was published, but the mechanism of SORT-LNP is still unclear. Therefore, in this PNAS paper, in order to understand how SORT-LNP breaks through the delivery barrier of liver accumulation, the team studied the mechanisms that define its organ targeting characteristics.

First of all, according to the three established principles for determining the efficacy of liver targeting LNPs, the team identified and studied the mechanism factors that can explain the organ targeting characteristics of SORT-LNP: organ-level biological distribution, acid dissociation constant (pKa), and serum protein adsorption.

The team found that these three factors are different in different organ-targeted SORT-LNPs and are related to their tissue targeting characteristics. For example, the pKa of liver-targeted LNPs is close to 6.4. Apolipoprotein E (ApoE) is adsorbed on the surface of LNP.

In addition, the team provided evidence for the three-step mechanism of the functional role of serum proteins in tissue targeting. First, the desorption of PEG lipids on the surface of LNP exposed potential SORT molecules in LNP. Next, different serum proteins recognize exposed SORT molecules and adsorb them on the surface of LNP. Finally, the surface adsorbed proteins interact with homologous receptors expressed by cells in the target organs to promote the functional transmission of mRNA to these tissues.

These findings establish a key relationship between the molecular composition of SORT nanoparticles and their unique and accurate organ targeting properties, and show that the selection of SORT molecules determines which proteins can be adsorbed on the surface of LNP, thus affecting the delivery end point of SORT-LNPs.

In summary, this study explains the specific mechanism by which SORT-LNP implements organ-tissue specific delivery, which will optimize the therapeutic application of SORT-LNPs in tissues and organs such as lung, liver, and spleen, and lay the foundation for the expansion of SORT platform to other nanoparticle types, physiological tissues, and cell types.