Top 5 Breakthroughs in LNP Research in 2024
From overcoming blood-brain-barrier to more selective delivery, we've seen some truly exciting advancements in the LNP research field.
Lipid nanoparticles (LNPs) have emerged as a revolutionary tool in medicine, particularly highlighted by their role in the rapid development of mRNA vaccines against COVID-19. These nanometric delivery systems encase fragile genetic material, such as mRNA, and guide them safely into our cells. In 2024, we have witnessed some truly exciting discoveries in this field of nanotechnology. From our point of view, here we list five of the most important:
1. Fine-Tuning LNP Composition for Targeted Delivery
Traditionally, LNP formulations have followed a standard recipe: ionizable lipids, structural lipids, helper lipids and PEG-lipids. However, researchers are discovering that tweaking the proportions of the different lipids can have a major impact on where the LNPs go in the body. For example, Rampado et al. found that by increasing the amount of a helper lipid called DSPC (distearoylphosphatidylcholine) in the LNP, they could achieve enhanced delivery of mRNA to the colon in mice, while reducing accumulation in the liver and spleen. This type of fine-tuning opens the door to creating LNPs that target specific organs and tissues, potentially improving treatment for diseases like Inflammatory Bowel Disease (IBD).
2. Multi-Armed Ionizable Lipids for Enhanced Spleen Targeting
While the liver has been a primary target for LNP-based therapies due to the natural tropism towards hepatocytes, the spleen is another key therapeutic target given its abundant immune cell density and its contribution to haematopoiesis. Scientists have designed novel ionizable lipids with a "multi-armed" structure, which has shown improved targeted mRNA delivery to immune cells in the spleen. These dendron-like lipids have a branched structure that enhances their ability to endogenously target the spleen by adsorbing a series of hematopoietic and transmembrane transporter-related proteins, without the need for additional targeting molecules and the multi-step manufacturing hurdles they pose. LNPs with these comb-shaped lipids could be instrumental in developing next-gen mRNA vaccines and treatments that aim to stimulate the immune system.
3. Peptide-Guided LNPs for Brain Delivery
Getting drugs across the blood-brain barrier (BBB) has always been a major hurdle. Recently, Han et al. have shown that adding peptides to the surface of LNPs can enable them to cross the BBB and deliver mRNA to specific cell types in the brain, including neurons. Using LNPs linked with peptides that target receptors overexpressed on brain endothelial cells and neurons, researchers found enhanced mRNA transfection in the mouse brain and reduced hepatic delivery after systemic administration in mice. This is a massive step forward for potential treatments for neurodegenerative conditions such as Alzheimer's and Parkinson's.
4. Acid-Degradable LNPs for Fetal Brain Gene Editing
Treating diseases before birth is becoming closer to being technically feasible. Particularly, in utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders, using CRISPR/Cas9 machinery. However, availability of mRNA delivery vehicles that can efficiently transfect cells in the brain is lagging behind. To overcome these hurdles, scientists have developed acid-degradable LNPs (ADP-LNPs). ADP-LNPs are densely coated with a molecule called PEG, (polyethylene glycol), designed to detach from the lipids in acidic environment. These LNPs have shown great promise in delivering gene-editing tools into the fetal brain tissue in a safe and effective manner, yielding high transfection of mRNA and low toxicity, opening doors for treating neurodevelopmental disorders before birth.
5. Lipid Tail Length as a Key Factor in Organ Selectivity
It turns out that even subtle changes in the length of the lipid tails in LNPs can drastically affect their destination in the body. Research has shown that LNPs with different lipid tail lengths, but otherwise identical composition, exhibit different mRNA expression profiles in the liver and spleen. This discovery provides another strategy for modulating LNP biodistribution without the need for complex modifications or added molecules.
Bonus: Improving LNP Safety with AI
The Generative AI revolution has also reached nanotechnology. For instance, Mana.bio have developed a Machine Learning (ML) model to predict LNP safety characteristics, including cellular, immunological, haematological, and hepatotoxic hallmarks, in order to generate novel lipids and LNP compositions. Their unique ML model is trained with both curated public data and in-house experimental results, and is overseen by a platform that monitors both lab and computational performance in real-time, generating a library of data points from thousands of LNP formulations. Mana.bio’s iterative, AI-driven approach has led to new LNP candidates with improved tolerability while maintaining potency and specificity, for targets outside the liver.
Looking Ahead
The breakthroughs in LNP technology in 2024 have been truly remarkable. By fine-tuning the composition of LNPs, attaching targeting peptides, creating novel degradable and multi-armed lipids, and optimizing lipid tail lengths, scientists are demonstrating remarkable control over where these delivery vehicles go in the body. These developments suggest that we are on the cusp of a new era of targeted and effective mRNA therapeutics, not just for infectious diseases, but also for a wide range of other conditions, such as neurodegenerative diseases and IBD. Further research will undoubtedly refine these approaches, leading to even more sophisticated and potent treatments in the years to come.
Interested in learning more about LNPs?
Overcoming Liver Accumulation: Extrahepatic Targeting Strategies for Lipid Nanoparticles (LNPs)
New targeting strategies are showing how the accumulation of lipid nanoparticles (LNPs) in the liver can be reduced.