How to achieve target delivery of mRNA drugs to organs, cells, and tumors?-PII

Cell Targeted Delivery

In addition to organ-specific delivery, the researchers sought to target specific cell subpopulations in the liver by engineering ionizable lipid nanoparticles for selective delivery to hepatocytes and hepatic sinusoidal endothelial cells (LSECs). Increasing PEG content enhanced hepatocyte-targeted delivery, while adding mannose increased hepatic sinusoidal endothelial cell (LSEC) delivery.

Tumor Targeted Delivery

Because heterogeneity is one of the most important indicators of high cancer malignancy, efforts to eradicate cancer by targeting a single receptor are likely to fail, resulting in the proliferation of drug-resistant cancer cells once the specific targeting receptor is lost. Despite the widespread usage of monoclonal antibodies that precisely bind to cell surface receptors, chemical conjugation of several monoclonal antibodies to LNPs is inefficient and necessitates careful optimization of each monoclonal antibody.

Recently, a revolutionary strategy for engineering LNPs became accessible. ASSET is a membrane-anchored lipoprotein that binds to the antibody Fc structural domain and is integrated into RNA-loaded lipid nanoparticles. It has two functional domains: an N-terminal signal sequence followed by a short CDQSSS peptide NlpA motif that is lipidated in bacteria and a scFv of a monoclonal antibody (clone RG7/1.30) that binds to the IgG2a antibody's Fc constant region. This lipidation strategy, initially used to demonstrate proteins anchored to the inner membrane of E. coli, allows for the insertion of purified recombinant lipidated ASSET into any lipid vesicle. An mCherry structural domain and His tag are fused to the C-terminus of ASSET and used to track the uptake of LNPs (used experimentally) and ASSET purification. The LNPs bind to the antibody Fc and self-assemble into targeted LNPs in vivo after selecting the cells to be targeted. Mouse model investigations have validated the targeting specificity and effectiveness.

Commercialization Progress

ReCode Therapeutics is advancing the commercialization of SORT LNPs (currently in preclinical) and closed a Series B $80 million financing round on October 21, 2021, led by Pfizer Ventures and EcoR1 Capital with participation from Sanofi Ventures and others, with funds for SORT LNPs technology for clinical studies in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF).

Summary

The fundamental technique for maximizing efficacy and minimizing mRNA toxicity is to precisely transport mRNA to the target location. Targeted delivery to the lung, liver, and spleen, as well as precise targeting to individual cells, has been made possible thanks to modifications based on the physicochemical features of the delivery vector itself. Self-assembling LNPs, which were recently developed, can be self-assembled in vivo with specific targeting antibodies to accomplish precise targeting of cancer or inflammatory regions. Next-generation mRNA technology will focus on organ-targeted mRNA delivery.

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