Fig. 14
The cutting-edge development in the field of genetic drug delivery using self-assembled nanoparticles made from lipid and polymer materials. Currently, the most advanced system for delivering genetic drugs in clinical settings is lipid nanoparticles incorporating an ionizable lipid. These materials contain a tertiary amine that can acquire a charge at acidic pH, enabling the loading of nucleic acids during formulation and facilitating their release from endosomes after cellular uptake. Examples of ionizable lipids include Dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA) found in the FDA-approved drug Onpattro, LP-01 in Intellia Therapeutics' clinical candidates NTLA-2001 and NTLA-2002 for liver gene editing, and SM-102 and ALC-315, which are ionizable lipid components of the Moderna and Pfizer-BioNTech vaccines, respectively. Alternatively, certain polymers containing ionizable amine groups can also be utilized for nanoparticle formulation, with the choice of monomers affecting delivery efficiency and tissue selectivity. In both ionizable lipids and polymers, additional components can be added to enhance nanoparticle stability, fusogenicity (ability to merge with cellular membranes), and selectivity. Furthermore, the surfaces of these nanoparticles can be modified using synthetic or biological targeting ligands and stealth coatings to alter their circulation time, biodistribution, and cellular uptake. By loading nucleic acid biomolecules into nanoparticles, it becomes possible to reprogram the fundamental principles of biology through gene silencing, expression, and editing to correct disease processes. 18:1 PA (1,2-dioleoyl-sn-glycero-3-phosphatidic acid), CART (charge-altering releasable transporter), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DOTAP (1,2-dioleoyl-3-trimethylammonium-propane), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), PBAE (poly(beta-amino ester)), PEI (polyethyleneimine), SORT (selective organ targeting). Reprint from [200] with a permission from Springer Nature