FDA Approved Lipid for Nanoparticles: Revolutionizing RNA Vaccine and siRNA Therapy

Lipid nanoparticles (LNPs) have been one of the most revolutionary drug delivery technologies, especially for RNA therapy. These nanoparticles are made from lipids that have nucleic acids like mRNA or siRNA, so they can be delivered to the cell efficiently. LNPs are changing the landscape of genetic treatments and vaccines delivery.

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Lipid Nanoparticles for Drug Delivery

Lipid nanoparticles are now the gold standard for RNA delivery because they protect delicate RNA molecules from damage and improve uptake into cells. They are usually a combination of ionizable cationic lipids, neutral phospholipids, cholesterol and PEGylated lipids. Each element contributes a unique function in the stability and function of the nanoparticle so that it can function during drug delivery. The creation of LNPs is dependent on lipid selection.

Lipid Nanoparticle Components

The primary components used in LNP formulations include:

• Ionizable Cationic Lipids: Lipids are important for encapsulating RNA. They positively charge in acid, which allows the LNPs to engage negatively charged RNA molecules. When they reach the acidic interior of the endosomes, the ionizable lipids release RNA by breaking open the endosomal membrane.
• Neutral Phospholipids: Phospholipids such as DSPC (distearoylphosphatidylcholine) are included to stabilize the lipid bilayer and contribute to membrane fusion, enhancing the release of RNA into the cytoplasm of the target cells.
• Cholesterol: Cholesterol is crucial for stabilizing the lipid bilayer structure of LNPs. It provides flexibility and fluidity, allowing the nanoparticles to maintain their integrity during circulation and interact effectively with cellular membranes.
• PEGylated Lipids: Lipids such as PEG2000-DMG are used to coat the LNPs, helping to evade the immune system and prolong circulation time in the bloodstream. PEGylation reduces protein binding and minimizes clearance by the mononuclear phagocyte system (MPS).

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FDA Approved Lipid for Nanoparticles

The increasing success of lipid nanoparticles is driven by their versatility and efficiency in delivering therapeutic RNA, including mRNA vaccines and gene-silencing small interfering RNA (siRNA) therapies. The FDA approval of various lipid nanoparticle formulations marks a significant milestone in the field of nanomedicine, where these systems have been employed to safely and effectively deliver highly sensitive biomolecules, such as mRNA, siRNA, and DNA, to target cells with precision. These FDA-approved lipid nanoparticles are transforming the landscape of modern medicine, enabling the development of groundbreaking treatments for genetic disorders, cancers, and infectious diseases.

Timeline of some important events for LNP development. (Hajiaghapour, A.M.; et al, 2023)

Patisiran (Onpattro): First FDA-Approved RNAi Therapeutic

Patisiran (Onpattro), developed by Alnylam Pharmaceuticals, was the first FDA-approved therapeutic to use lipid nanoparticles for the delivery of small interfering RNA (siRNA) to target the transthyretin (TTR) gene. This groundbreaking RNA interference (RNAi) therapy targets hereditary transthyretin-mediated amyloidosis (hATTR), a rare genetic disorder characterized by the accumulation of amyloid deposits in various organs, leading to life-threatening complications, particularly in the heart and nervous system.

• The lipid nanoparticle formulation used in Patisiran consists of a carefully optimized mixture of DLin-MC3-DMA, DSPC (distearoylphosphatidylcholine), cholesterol, and PEG2000-DMG (polyethylene glycol). This combination ensures efficient encapsulation and stabilization of siRNA, while also enhancing its ability to evade immune system recognition and prolong its circulation time in the bloodstream. The ratio of these lipids (50:10:38.5:1.5) was specifically chosen to maximize the delivery of the siRNA to the liver, where TTR is predominantly produced.

Patisiran's approval in 2018 represented a significant leap forward for RNAi therapies, illustrating how LNPs can be used as highly effective carriers for gene-silencing agents. This approval also established LNPs as a key component of gene therapies for rare diseases, setting the stage for similar approaches to treat other genetic disorders.

ARCT-154: Self-Amplifying mRNA Vaccine

Developed by Arcturus Therapeutics in collaboration with CSL and Meiji, ARCT-154 is a self-amplifying mRNA vaccine designed to protect against COVID-19. This vaccine utilizes a unique self-amplifying RNA technology that allows for less RNA to be required for the same immune response, making it more efficient in its use of genetic material. The lipid nanoparticle formulation for ARCT-154 consists of ATX-126, DSPC, cholesterol, and PEG2000-DMG in a ratio of 50:7:40:3.

• The self-amplifying mRNA is encoded to produce the spike protein of the SARS-CoV-2 virus. By introducing this mRNA into the body through lipid nanoparticles, ARCT-154 is able to trigger an immune response that teaches the body to recognize and combat the virus if it is encountered in the future. This self-amplifying mRNA platform is advantageous because it requires lower RNA doses, which can potentially reduce side effects and manufacturing costs while maintaining high efficacy.

The development of ARCT-154 highlights how lipid nanoparticles can be tailored to suit specific types of RNA, including self-amplifying RNA vaccines. This self-amplifying approach is part of a broader trend to optimize RNA delivery systems, making vaccines and therapies more efficient and scalable, especially in the context of global health emergencies like the COVID-19 pandemic.

BNT162b2 (Comirnaty): Pfizer/BioNTech's COVID-19 mRNA Vaccine

The BNT162b2 vaccine, marketed under the name Comirnaty, was developed by Pfizer and BioNTech to combat the COVID-19 pandemic. This vaccine was one of the first to receive emergency use authorization (EUA) from the FDA and was later fully approved for use. The vaccine uses lipid nanoparticles to deliver mRNA encoding the spike protein of the SARS-CoV-2 virus, triggering an immune response that prepares the body to fight off the virus if it is encountered.

• The lipid nanoparticle formulation for BNT162b2 includes ALC-0315, DSPC, cholesterol, and ALC-0159, with a specific ratio of 46.3:9.4:42.7:1.6. The ionizable lipid, ALC-0315, is designed to interact with the negatively charged mRNA, facilitating its encapsulation and protection from degradation. The inclusion of cholesterol enhances the structural integrity of the nanoparticles, while PEG2000-DMG helps to prolong circulation time and reduce immune clearance.

Comirnaty's success has demonstrated the effectiveness of lipid nanoparticles in the rapid delivery of mRNA vaccines, allowing for quick adaptation and development in response to emerging infectious diseases. The approval of BNT162b2 has not only been a triumph for COVID-19 vaccine development but also for the broader field of RNA therapeutics, as it paves the way for future mRNA-based treatments.

mRNA-1273 (Spikevax): Moderna's mRNA Vaccine for COVID-19

Similar to BNT162b2, mRNA-1273 (branded as Spikevax) is Moderna's mRNA-based vaccine against COVID-19. The lipid nanoparticles used in this vaccine also deliver mRNA encoding the SARS-CoV-2 spike protein, triggering an immune response. The lipid composition for mRNA-1273 includes SM-102, DSPC, cholesterol, and PEG2000-DMG in a lipid ratio of 50:10:38.5:1.5, similar to that used in BNT162b2.

• The mRNA-1273 vaccine demonstrated similar efficacy and safety profiles as BNT162b2 during clinical trials, with an efficacy of approximately 94% in preventing symptomatic COVID-19 infection. The lipid nanoparticle formulation in Spikevax is critical for ensuring that the mRNA remains intact during its journey to cells, where it is translated into the spike protein. This protein then triggers an immune response, which primes the body's immune system to recognize and neutralize the virus if encountered in the future.

Moderna's success with Spikevax further solidified the role of lipid nanoparticles in the mRNA vaccine space, highlighting their importance in the rapid and scalable production of vaccines against infectious diseases. The continued evolution of lipid nanoparticle formulations will undoubtedly enhance the efficacy, safety, and accessibility of future mRNA vaccines.

mRNA-1345 (mRESVIA): Moderna's RSV Vaccine

In addition to its COVID-19 vaccines, Moderna has also developed mRNA-1345, branded as mRESVIA, a vaccine targeting respiratory syncytial virus (RSV), a common cause of respiratory illness, particularly in infants and elderly populations. The lipid nanoparticles used in mRNA-1345 include SM-102, DSPC, cholesterol, and PEG2000-DMG, although the exact lipid ratio is not publicly disclosed. This formulation is similar to that used in the company's COVID-19 vaccines, optimized for the efficient delivery of mRNA to cells.

• The vaccine works by delivering mRNA that encodes the RSV F protein, which is recognized by the immune system as foreign and triggers the production of antibodies that can neutralize the virus. The success of mRNA vaccines like mRNA-1345 demonstrates how lipid nanoparticles can be adapted for different types of viral infections and underscore their importance in the next generation of viral vaccines.

FDA-approved lipid nanoparticles have become a critical technology in the development of RNA-based therapeutics and vaccines. The success of Patisiran, ARCT-154, BNT162b2, mRNA-1273, and mRNA-1345 showcases the diverse applications of lipid nanoparticles across a range of therapeutic areas, from rare genetic diseases to infectious diseases like COVID-19 and RSV. These lipid formulations offer a powerful means of delivering sensitive genetic material to target cells, opening the door to new treatments for previously untreatable conditions.

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Applications of FDA Approved Lipid for Nanoparticles

Lipid nanoparticles have demonstrated significant promise across various therapeutic areas, offering versatile solutions for drug delivery, gene therapy, and vaccine development.

Lipid Nanoparticles as Drug Carrier

Lipid nanoparticles (LNPs) provide an efficient, non-toxic delivery system for various drugs, particularly RNA or DNA-based therapies. They protect fragile therapeutic molecules from degradation, enhance cellular uptake, and enable controlled release at target sites. Beyond RNA therapies, LNPs are being explored for small molecules, chemotherapeutics, and biologics.

A key example is Patisiran, which uses LNPs to deliver siRNA that silences the TTR gene, offering a breakthrough treatment for genetic disorders like hATTR. This demonstrates LNPs' ability to precisely target tissues, providing new treatment options for rare diseases.

Lipid Nanoparticles for Gene Therapy

LNPs have revolutionized gene therapy by enabling the safe and effective delivery of genetic material (DNA or RNA) to cells. Patisiran exemplifies this, showing how LNPs can silence specific genes to treat previously untreatable conditions. Additionally, LNPs are crucial in developing self-amplifying mRNA vaccines, such as ARCT-154, which rely on precise lipid formulations for RNA stability and efficient cellular delivery.

Lipid Nanoparticles for Vaccines

LNPs play a key role in mRNA vaccines, notably for COVID-19 with BNT162b2 and mRNA-1273, where they encapsulate mRNA, facilitating delivery to cells to trigger an immune response. LNPs are also being explored for mRNA vaccines against other infectious diseases (e.g., RSV) and even cancer. Their versatility makes LNPs ideal for next-generation vaccines, offering scalable and efficient solutions to global health challenges.

Reference

1. Hajiaghapour, A.M.; et al. Lipid Nanoparticles as Promising Carriers for mRNA Vaccines for Viral Lung Infections. Pharmaceutics. 2023, 15(4): 1127.