Lipid nanoparticles (LNPs) are nanoscale lipid-based vesicles, typically around 100 nm in diameter, used for delivering various therapeutic agents. They are composed of four key lipid components: ionizable lipids, phospholipids, cholesterol, and PEGylated lipids. LNPs offer a promising platform for delivering nucleic acids (like mRNA, siRNA and antisense oligonucleotides) and other therapeutics due to their ability to protect the cargo, enhance cellular uptake, and improve stability in the bloodstream.

Clinical Applications of LNPs

Several RNA-based therapeutics and vaccines use lipid nanoparticles (LNPs) for delivery and have received regulatory approval.

In gene therapy, LNPs have revolutionized the delivery of nucleic acid drugs, particularly siRNA, by overcoming challenges like degradation and poor cellular uptake. Patisiran (ONPATTRO), the first FDA-approved LNP-formulated siRNA drug, treats hereditary transthyretin amyloidosis (hATTR) by delivering siRNA to reduce transthyretin protein levels, alleviating disease symptoms.

In mRNA vaccines, the COVID-19 pandemic accelerated the adoption of LNP-mRNA technology, with Moderna and BioNTech using LNPs to deliver mRNA encoding the SARS-CoV-2 antigen for their vaccines. This technology efficiently triggered an immune response, demonstrating mRNA vaccines' potential and paving the way for their widespread use in global vaccination efforts. The success of these vaccines, coupled with the efficiency of LNPs, has made them a focal point in biopharmaceutical research, sparking interest in their application for other vaccines and cancer therapies.

Table 1. Marketed RNA-LNP Products

The Challenges of LNP Development and Manufacturing

Inefficient Endosomal Escape

LNPs have low efficiency in releasing nucleic acids inside cells. LNPs internalize into cells through various endocytosis mechanisms and are then transported to early endosomes, which mature into late endosomes and eventually lysosomes. For efficient delivery, the nucleic acid payloads must be released into the cytosol before the late endosomes mature into lysosomes, where enzymatic degradation occurs. This critical step, known as endosomal escape, is essential for the drug’s function. However, the currently limited efficiency of payload endosomal escape represents a significant bottleneck hindering the application and development of mRNA and other nucleic acid-based therapeutics.

Liver Accumulation

Another limitation is LNPs' tendency to accumulate in the liver upon intravenous administration, which restricts the effective delivery of nucleic acid drugs to organs outside the liver, such as the lungs, brain, and other tissues, making precise targeting challenging. This liver-specific tropism relies on interactions with serum proteins, like apolipoprotein E (ApoE), and the liver's unique anatomy and function. When administered systemically, LNPs quickly bind to ApoE, which helps direct them to liver cells through the low-density lipoprotein (LDL) receptor. The liver's role in the reticuloendothelial system (RES) also supports ApoE-mediated targeting. However, Kupffer cells, the liver’s macrophages that filter nanoparticles from the blood, play a dual role: they aid in liver targeting but may also lower therapeutic effectiveness by trapping LNPs before they can reach hepatocytes.

Challenges in Cationic Lipid Screening

The ideal cationic lipid should bind to nucleic acids effectively, facilitate cellular uptake, and minimize toxicity. However, finding suitable cationic lipid molecules is challenging, and there are few viable options. Since 2015, despite ongoing efforts by research teams, only a limited number of cationic lipids have shown potential for practical application.

Challenges in LNP Preparation

The preparation of LNPs also presents significant hurdles. The film hydration method is sensitive to lipid concentration and buffer composition, often resulting in inconsistent particle sizes and poor stability. While microfluidic technology is indeed costly and faces challenges in scaling up for large-scale production. The ethanol injection method, on the other hand, can leave residual ethanol, compromising both safety and stability, while also increasing production costs and complicating quality control.

Conclusion

In conclusion, lipid nanoparticles are a cornerstone of modern drug delivery, particularly in the rapidly evolving landscape of RNA-based therapeutics. While challenges in endosomal escape, biodistribution, and manufacturing persist, the ongoing innovation in lipid chemistry and formulation strategies holds immense promise. As researchers continue to refine LNP design and overcome these hurdles, we can anticipate even broader clinical applications and a future where these nanoscale carriers unlock the full potential of next-generation medicines.

References
[1] S. Chatterjee, E. Kon, P. Sharma, & D. Peer, Endosomal escape: A bottleneck for LNP-mediated therapeutics, Proc. Natl. Acad. Sci. U.S.A. 121 (11) e2307800120, https://doi.org/10.1073/pnas.2307800120 (2024). 
[2] Hosseini-Kharat M, Bremmell KE, Prestidge CA. Why do lipid nanoparticles target the liver? Understanding of biodistribution and liver-specific tropism. Mol Ther Methods Clin Dev. 2025 Feb 15;33(1):101436. doi: 10.1016/j.omtm.2025.101436. PMID: 40104152; PMCID: PMC11919328.

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