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

Abstract

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.

Silicon Ether Ionizable Lipids Enable Potent mRNA Lipid Nanoparticles with Rapid Tissue Clearance

“…We initially tried an ortho ester ( Figure S1 ), as these are known to undergo hydrolysis and similar cleavable linkers have previously been used in PEG-lipids. 44 − 47 However, we found that these structures were too unstable or reactive for our purposes. As an alternative, silicon is in the same group of the periodic table as carbon (the central atom in ortho esters) but with decreased reactivity due to larger atomic radii and differing electron orbital occupancy.…”

“…With this context, we sought to design a series of ionizable lipids possessing the design features and high potency of our own benchmark Lipid 10, while engineering in rapid clearance using a chemistry that did not rely on esterases. We initially tried an ortho ester (Figure S1), as these are known to undergo hydrolysis and similar cleavable linkers have previously been used in PEG-lipids. − However, we found that these structures were too unstable or reactive for our purposes. As an alternative, silicon is in the same group of the periodic table as carbon (the central atom in ortho esters) but with decreased reactivity due to larger atomic radii and differing electron orbital occupancy.…”

Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer’s Disease Management

“…Liposomes, a lipid-based vesicular nanocarrier, have versatile applications, including gene delivery, therapeutic administration, and nucleic acid delivery to the brain [ 109 ]. Liposomes serve as ideal carriers for gene delivery, benefiting from the incorporation of ionizable or fusogenic lipids, which enhance endosomal escape, target specificity, diminish immunogenicity, and extend circulation time [ 110 ]. However, the presence of lipids in liposomes yields a dual-edge characteristic, conferring biocompatibility while also increasing susceptibility to peroxidation and leakage, leading to compromised stability and shelf life.…”

Delivery of nucleic acids using nanomaterials

“…For example, it is widely believed that some cationic polymers interact with the endosomal membrane through the “proton sponge effect” and subsequently disrupt it (which will be described in detail in the corresponding section) [ 95 ]. This interaction can also be achieved using ionizable lipids, as these pH-sensitive lipids can be protonated in acidic environments, acquiring a positive charge [ 96 ]. It is worth noting that some helper lipids can also be protonated in acidic environments.…”