Lipid nanoparticles (LNPs) are one of the most prominent tools for nucleic acid delivery. Their versatility allows the encapsulation of different cargos (siRNA, miRNA, AONs, mRNA, DNA) to address multiple disease models (cancer, infections, neurodegenerative disorders, etc.). Herein, we summarise some of the main applications of LNPs and the latest developments in the encapsulation and delivery of different nucleic acids.
Lipid Nanoparticles
LNPs is a broad term encompassing different lipid-based structures. Herein, we will present a brief history of the evolution that led to the development of LNPs for COVID-19 vaccines.
Liposomes were one of the first nanoparticles used for drug delivery. They can be of different lamellarity and sizes (~ 50-250 nm for drug delivery) and can encapsulate both hydrophobic and hydrophilic molecules. Liposomes provide high loading capacity and biocompatibility. However, they remain fragile (sensitive to hydrolysis and oxidation), with a rapid circulation time due to their interactions with high- and low-density lipoproteins (HDL and LDL). To overcome these barriers, extensive work on the physicochemical properties of liposomes has been conducted over the years, which has revealed critical parameters regarding lipid-based delivery systems (Hald 2022):
- Cholesterol reduces the transfer of phospholipids to HDL, thereby increasing the residence time of liposomes in plasma, while also being critical to the structure of the LNP.
- LNPs with saturated fatty acyl chains are more stable in the blood than unsaturated ones; however, this stability must be balanced against the importance of unsaturated chains in fusogenicity.
- Particle size influences LNPs’ stability, with smaller vesicles having longer half-life compared to larger ones.
- Net charge of LNPs influences their half-life, with negatively charged liposomes being less stable than neutral liposomes, whereas positively charged particles are more toxic and quickly removed from circulation.
As a result, liposomes have been successfully used in clinical trials, albeit for small drug delivery only (i.e. daunorubicin, doxorubicin). However, despite improvements, liposomes remain unstable in vivo as they bind to other serum components. To limit this phenomenon, liposomes can be coated with inert molecules by introducing PEGylated lipid into liposome preparations, creating “Stealth” liposomes for drug delivery. Yet, these systems are only suitable for the delivery of small drugs (Doxorubicin, DOXIL®).
