Lipid nanoparticles have proven their value with innovative nanomedicines already approved for market use, demonstrating their transformative potential in drug delivery. 

Despite these advancements, lipid nanoparticle development for clinical applications still faces numerous challenges, such as lipid component selection, the enhancement of stability and targeting capabilities. This blog explores these complexities and highlights innovative strategies for optimizing the efficacy and safety of lipid nanoparticles.

Strategic Approaches to Lipid Nanoparticle Development and Optimized Targeting Capabilities 

Lipid nanoparticles possess the capability to encapsulate, stabilize, and deliver nucleic acid payloads intracellularly, thereby significantly improving the therapeutic efficacy of these genetic molecules and facilitating the development of innovative treatments. These include siRNA-based therapies for liver-related diseases, such as Onpattro® for hereditary transthyretin-mediated amyloidosis, and mRNA-based vaccines, notably Moderna’s mRNA-1273 and Pfizer-BioNTech’s BNT162b2, which have been the pillar of contrasting the COVID-19 pandemic [1,2].

However, lipid nanoparticle development presents substantial challenges, especially for extrahepatic delivery. Intravenously administered nanoparticles are subject to rapid hepatic accumulation while targeting specific extrahepatic cell types has become more challenging. The effectiveness of nanomedicines critically depends on the efficient delivery of nucleic acid payloads to target cells, a process significantly influenced by the physicochemical properties of the nanoparticles, such as size, charge, and surface properties. 

One of the primary obstacles to the efficient delivery of nucleic acid payloads to target cells is the formation of protein corona, this term refers to the layer of biomolecules that adsorb onto the surface of lipid nanoparticles (LNPs) when they come into contact with biological fluids such as blood plasma. The specific composition and properties of the protein corona can significantly impact LNPs’ in vivo fate, affecting their blood circulation, cellular uptake, cytotoxicity, and biodistribution [3].

Various targeting strategies are under investigation to enhance the delivery efficiency of nanoparticles and their payload to non-hepatic tissues [4]. These strategies can be broadly categorized into active and passive targeting approaches.

• • Active targeting involves grafting targeting ligands such as antibodies, peptides, antibody fragments, or aptamers, among others, onto the nanoparticle surface. These ligands are designed to interact specifically with molecular entities on the surface of the targeted cells, thereby facilitating specific delivery.

• • Passive targeting relies on modulating the lipid composition, among other strategies, to achieve desired surface properties, influencing their interaction with blood components and biodistribution.

The Role of Materials

The materials and methods used in lipid nanoparticle development are critical determinants of their efficacy and safety. The primary components of lipid nanoparticles include ionizable cationic lipids, helper lipids, cholesterol, and polyethylene glycol (PEG)-lipids. Each of these components plays a specific role in the structure and function, as we have recently reviewed [5].

Ionizable cationic lipids are indispensable in lipid nanoparticle development, as they facilitate the encapsulation of nucleic acids. The apparent pKa of these lipids is a key attribute that influences their performance, as it affects the ionization state of the lipid in different environments, thereby modulating the encapsulation efficiency and subsequent intracellular delivery.  

Lipids, such as 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, contribute to the structural integrity and stability. In particular, cholesterol enhances the fluidity and permeability of the lipid bilayer, while PEG-lipids provide a steric barrier that prolongs the circulation time by reducing opsonization and subsequent clearance by the reticuloendothelial system (RES).

The preparation of lipid nanoparticles typically involves rapidly mixing lipid components under controlled conditions to form stable nanoparticles. Techniques such as microfluidic and ethanol injection are commonly employed to ensure uniformity and precise control over nanoparticle size.

A standout feature of DIVERSA’s technology is its ease of use and specific composition, using cell membrane lipids for improved interaction and transfection efficiency, and specific lipids for stabilizing purposes.

References

1. Akinc, A.; Maier, M.A.; Manoharan, M.; Fitzgerald, K.; Jayaraman, M.; Barros, S.; Ansell, S.; Du, X.; Hope, M.J.; Madden, T.D.; et al. The Onpattro Story and the Clinical Translation of Nanomedicines Containing Nucleic Acid-Based Drugs. Nat Nanotechnol 2019, 14, 1084–1087, doi:10.1038/s41565-019-0591-y.
2. Schoenmaker, L.; Witzigmann, D.; Kulkarni, J.A.; Verbeke, R.; Kersten, G.; Jiskoot, W.; Crommelin, D.J.A. mRNA-Lipid Nanoparticle COVID-19 Vaccines: Structure and Stability. International Journal of Pharmaceutics 2021, 601, 120586, doi:10.1016/j.ijpharm.2021.120586. 
3.   Wang, S.; Zhang, J.; Zhou, H.; Lu, Y.C.; Jin, X.; Luo, L.; You, J. The Role of Protein Corona on Nanodrugs for Organ-Targeting and Its Prospects of Application. J Control Release 2023, 360, 15–43, doi:10.1016/j.jconrel.2023.06.014.
4. Simonsen, J.B. Lipid Nanoparticle-Based Strategies for Extrahepatic Delivery of Nucleic Acid Therapies – Challenges and Opportunities. Journal of Controlled Release 2024, 370, 763–772, doi:10.1016/j.jconrel.2024.04.022.
5. Taina-González, L.; de la Fuente, M. The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA. Pharmaceutics 2022, 14, 460, doi:10.3390/pharmaceutics14020460.