Expanding Therapeutic Reach: Antibody-Conjugated Lipid Nanoparticles to Enhance Extrahepatic Nucleic Acid Delivery

Bei Cheng, Annette Bak, Sabrina Khan, Sanjib Saha, Dominic Kabbabe, Michael Grondine, Liping Zhou.

mRNA therapeutics are a new modality, and before the two COVID vaccines were launched, it was a niche area in drug development. Now the modality is being used for many purposes in drug discovery and development pipelines. The contemporary delivery system for mRNA is Lipid Nanoparticles (LNPs). LNPs classically consists of an ionizable lipid, PEG lipid, phospholipid & cholesterol. Unless designed otherwise LNPs have a natural affinity to accumulate in the liver, since it functions as a biological filtration system to sequester a large fraction of administered nanoparticles. It has been demonstrated that apolipoprotein E (ApoE), when adsorbed onto the LNP surface, generate a protein corona, and plays a major role in hepatocellular LNP uptake via the LDLR receptor.

But what about diseases outside the liver? Brain, heart, muscle spleen plus more that could benefit from a mRNA therapeutic. There are strategies to avoid liver uptake for LNPs and further uptake in other tissues – they evolve around tailoring the composition of the LNP to reduce liver and enhance an alternate tissue tropism. And then there are of course active targeting, where a ligand is grafted to the LNP to actively direct it towards for example a receptor on the surface of cells in the desired tissue. Such a strategy will allow mRNA loaded LNPs to be used for example for in vivo gene editing or CAR T cell generation in non-liver tissue.

The presentation will highlight the importance of the protein corona, the main strategies for designing LNPs for non-liver tissues, and will be complemented by case studies to illustrate the principles.