In 2018, the FDA approved the first gene drug based on lipid nanoparticles (LNPs), the siRNA Patiiran (ONPATTRO; Alnylam), for the treatment of polyneuropathy caused by hereditary transthyroxine-mediated amyloidosis. LNPs had been studied as delivery tools for decades before that approval, but they gained wider attention for a different reason: they turned out to be a workable technical platform for delivering mRNA, a shift reviewed in MRNA-based Therapies: Present.
LNPs typically consist of four components: cationic or ionized lipids, cholesterol, auxiliary lipids, and polyethylene glycol lipids. The ionizable lipid changes charge with pH, condensing nucleic acid at low pH and releasing it in the cytosol; cholesterol and the auxiliary lipid set the particle's physical behaviour, and the PEG lipid controls size and circulation time. Together these components enable the encapsulation of various drugs, including small molecules, peptides, and nucleic acids, protecting them from degradation by enzymes and facilitating their transport across cell membranes. LNPs also support repeated and immediate administration, and their safety has been validated through the widespread use of COVID-19 vaccines.
Four Categories Of Gene Drugs
Based on their potential mechanisms of action, gene drugs can be categorized into four types.
The first is gene addition or substitution, involving the use of LNPs to deliver viral vectors containing specific genes, or mRNA encoding genes. The second is gene expression control, which includes LNPs encapsulating siRNA, or siRNA coupled with the hepatocyte targeting ligand GalNAc (N-acetylgalactosamine). The third is gene editing, which employs viral vectors or LNPs to deliver components of the CRISPR-Cas9 gene editing system. The fourth is DNA or RNA vaccines, such as mRNA vaccines encapsulated in LNPs or polymer nanoparticles.
The four differ in what the vehicle has to accomplish: transient expression in many cells for a vaccine, durable expression in a defined tissue for gene addition, a brief pulse of nuclease activity for editing. The same particle chemistry therefore performs unevenly across them.
Where LNPs Sit In The Pipeline
To understand the current and future significance of LNPs in the in vivo development of gene drugs, an analysis was conducted on publicly available information covering clinical and approved gene drug pipelines worldwide. It encompassed 538 assets from 273 companies as of December 2021, and looked at how far LNPs have spread through the development pipeline and at the global market for LNP-based gene drugs from 2021 to 2036.
Among the four types, LNPs show the highest average penetration rate, defined as the percentage of assets employing this approach, in nucleic acid-based vaccines and gene editing, at 7%. That figure reflects the difficulty of GalNAc coupling when larger nucleic acids have to be delivered in those settings. Penetration in gene addition or substitution is relatively low, since adeno-associated virus (AAV)-based delivery offers greater utility there, an area covered in The Role of AAV in Gene Therapy: Immune Responses and Toxicity. Gene expression control shows the lowest penetration, largely because GalNAc coupling competes well on its own for hepatocyte targets. Overall, the LNP-initiated gene drug pipeline concentrates on DNA and RNA vaccines, mostly at phase I.
Market Size And The Next Decade
The current market size of LNP-supported gene drugs is estimated at around $51 billion, driven mainly by revenue from two COVID-19 mRNA vaccines, with Onpattro making up the remainder. In the short term that figure may shrink as COVID-19 vaccine revenue declines.
The expectation is that as the gene drug pipeline matures, companies will invest further in LNP innovation, and the market will grow again. By 2036, the LNP gene drug market is projected to rebound to $48 billion. Over that decade, sales of mRNA vaccines and co-stimulants in the COVID-19 context are expected to dominate the LNP market, while in vivo gene editing should take some share as products from companies such as Intellia Therapeutics and Beam Therapeutics reach approval.
What Has To Change For Broader Use
LNPs will continue to serve as a core tool for gene drugs, particularly mRNA vaccines. The broader application of LNPs beyond vaccines will depend on whether companies can tailor lipids for specific organs other than the liver. Work in that direction is already visible in Prisys Biotechnology: Novel Lipid Nanoparticles For MRNA Delivery in Primates.
Other factors could also widen adoption, including the capacity to encapsulate larger genes, particularly those exceeding 5kB in size, which is the packaging limit for many AAV vectors.
The current generation of LNPs has been clinically verified and widely used in mRNA vaccines, yet limitations remain in delivery efficiency, immunogenicity, shelf life and other application costs. The next generation may use novel non-lipid components, such as fusion proteins and polymers, to address them. In summary, LNPs hold the potential to evolve into a long-term fundamental drug delivery system, with extensive application prospects in gene medicine.
For teams moving an LNP programme toward preclinical testing, those questions become practical: circulation time, where the payload ends up, and repeat-dose tolerance. Prisys Biotech runs that work in non-human primates and other species, from NHP Pharmacology study design through Biodistribution Imaging Service readouts, with bioanalysis of LNP-formulated drugs handled in the same programme.
