Key Design Features of Lipid Nanoparticles and Electrostatic Charge-Based Lipid Nanoparticle Targeting

Lipid nanoparticles (LNP) have gained much attention after the approval of mRNA COVID-19 vaccines. The considerable number of currently ongoing clinical studies are testament to this fact. These efforts towards the development of LNPs warrant an insight into the fundamental developmental aspects of such systems. In this review, we discuss the key design aspects that confer efficacy to a LNP delivery system, i.e., potency, biodegradability, and immunogenicity. We also cover the underlying considerations regarding the route of administration and targeting of LNPs to hepatic and non-hepatic targets. Furthermore, since LNP efficacy is also a function of drug/nucleic acid release within endosomes, we take a holistic view of charged-based targeting approaches of LNPs not only in the context of endosomal escape but also in relation to other comparable target cell internalization strategies. Electrostatic charge-based interactions have been used in the past as a potential strategy to enhance the drug release from pH-sensitive liposomes. In this review, we cover such strategies around endosomal escape and cell internalization in low pH tumor micro-environments.