Considerations on antibody-based active targeting strategies for lipid nanoparticle delivery systems

Lipid nanoparticles (LNPs) as non-viral delivery vectors for nucleic acid therapeutics have become one of the leading technologies for gene therapy and vaccine applications following the development of the COVID-19 mRNA vaccines. Despite the success LNPs have achieved in the clinic, achieving cell or tissue specific delivery remains one of the greatest challenges of these delivery systems. To address this limitation, active targeting strategies involving grafting targeting ligands, in particular, antibody-labelled LNPs have been developed to achieve organ specificity through cell surface receptor mediated uptake following systemic delivery. While active targeting strategies using antibody decorated LNPs have shown promising efficacy in preclinical studies, clinical translation has yet to be realized. This mini-review will discuss the basic principles of systemic delivery of LNPs, followed by evaluation of historical and recent literature on active targeting strategies, and finally critically assess whether antibody-functionalized LNPs can be translated into the clinic. This will include discussion on early immunoliposome research which highlights obstacles in scale-up, manufacturing, and reproducibility of antibody-labelled liposomes for targeting solid cancers, as well as considerations that need to be addressed for designing targeting LNPs. We will highlight more recent strategies and preclinical efforts for using antibody-LNPs to target circulating immune cells and away from targeting disease organs themselves. Lastly, we will provide a brief perspective towards the feasibility of antibody-targeting and other targeting approaches to realize extrahepatic delivery.