Delivery Makes the Medicine
Innovation in lipid nanoparticles (LNPs) is enabling the next generation of nucleic acid medicines.
We’ve reached an age of complex medicines: antibody-drug conjugates, proteolysis-targeting chimeras (PROTACs), and nucleic acid medicines, to name just a few. Many of these advanced drug systems harness multiple components to deliver therapeutic payloads to specific targets.
While it’s easy to prioritize payloads — they are the components that modify disease biology — therapeutic efficacy and safety hinge on delivery. These components must work together as a seamless unit. In other words, a sound delivery mechanism is just as important as a cargo’s mechanism of action.
What’s more, although nucleic acid therapies promise programmability, by virtue of changing sequence to change the protein made or knocked down, doing that in the right cell has been the main technological roadblock to unleashing broad potential of this category of medicines.
This is where advanced LNPs are becoming essential. Rather than treating LNPs as commoditized packaging, or rebuilding bespoke particles from scratch for each therapeutic application, new efforts that could customize LNPs around payload, targeting moiety, tissue, and development needs while supporting the most important medicinal traits — potency, cell-selectivity, tolerability, redosability, manufacturability, and functional biology — would be a tremendous advantage.
This is the position Flagship-founded Mirai Bio has staked out with its approach: next generation LNPs that do more than carry cargo. These particles are built to integrate multiple functions that nucleic acid medicines require to work in vivo, from protecting the payload from degradation and reaching only the target tissues to supporting tolerability, manufacturability, and functional biological activity. In that sense, the LNP becomes more than a delivery vehicle. It becomes part of the therapeutic system itself, essential to the translation of a promising nucleic acid medicine from concept to in vivo performance.
Moving Beyond Passive Packaging
LNPs are often typecast as having one job — packing therapeutic nucleic acids for delivery. But that’s a vast oversimplification. LNPs have multiple components (including lipids, polymers, and chemical or protein ligands) and functions, including cargo protection, tissue/cell selectivity, liver detargeting, intracellular delivery, and tolerability enhancement.
Co-optimizing all of these components while checking all these functional boxes requires intensive bioengineering. Mirai is leveraging machine learning expertise — informed by enormous, proprietary in vivo datasets — to iteratively develop precise LNPs. This robust design and optimization process creates LNPs that home in on targeted tissues while avoiding hepatic capture (Figure 1).
Mirai’s LNPs are built around a proprietary library of 1,000+ ionizable lipids that better encapsulate nucleic acid payloads, boost biocompatibility, and improve targeting. These are combined with polyethylene glycols, helper lipids, and other ingredients, dynamically mixing and matching to develop the ideal formulations for specific applications. By one estimate, there are 1027 possible combinations of biochemical features and compositions to explore when designing a single particle; through a combination of human and machine intelligence, Mirai efficiently searches the viable domains of this search space to find the optimal components.
These complex systems are then rigorously tested in animal models, required to ensure translatability to humans. The key is molecular barcoding. Similar to barcodes on retail products, these tags help researchers track and quantify particles. By barcoding each LNP, Mirai can pinpoint where these particles accumulate in animal models and which ones promote functional cargo delivery. This creates an ongoing test/refine/retest in vivo feedback loop to iteratively engineer LNPs that target cells/tissues of interest, all the while increasing the size of the in vivo database. The result is validated data on selectivity and functional biology, that then allows for evaluation of more complex attributes such as scale/process development and NHP tolerability (Figure 2). Machine learning loops are integrated at each step because the exploration, design, and evaluation spaces are vast and grow with each cycle.
This streamlined process generates high fidelity data that answers many of the questions associated with nucleic acid medicine creation. Does the particle accumulate in and deliver to the target tissue and not the liver? Is the package stable? Is the process scalable? Is the drug well-tolerated?
Targeting Immune Cells Through the Spleen
Immune cells are promising targets for nucleic acid medicines, which means LNPs must find their way to the spleen, where many immune cells traffic and interact. Through the processes described above, Mirai has formulated LNPs that preferentially accumulate in the spleen and not the liver. This minimizes the “first-pass effect,” during which the liver takes up and metabolizes the drug, dramatically reducing its bioavailability and potentially contributing to toxicity.
Developing LNPs with splenic affinity solves a variety of problems. Whether the payload is designed to modulate T cells, B cells, natural killers, or macrophages, the tissue destination remains the same. The cargo and targeting molecules may shift, but that doesn’t require time-consuming LNP re-engineering to ensure tolerability (Figure 3).
By adding antibodies, oligos, or other targeting molecules, these drugs can even more effectively target specific cells within the spleen. Separately, the LNP can carry therapeutic cargos, such as mRNA encoding a chimeric antigen receptor, to drive the intended biological effect. Because key tolerability and manufacturing questions have already been worked through at the base LNP level, drug developers do not have to start from scratch, creating a brand new LNP or heavily revising an existing one for each payload, ligand, or target. They can move rapidly into in vivo disease models for testing and ultimately into humans for clinical trials.
In other words, drug developers get a significant headstart on their drug candidate journeys. While identifying and developing lead nucleic acid medicines can take roughly 40 months by industry benchmarks, Mirai’s advanced LNP platform can compress that timeline to as little as 10 months.
Where to next?
Nucleic acid medicines have already become a cornerstone class of medicine. Genetic instructions, delivered to the right place, can silence disease-causing genes, instruct cells to manufacture protective proteins, and generate therapeutic immune responses. These achievements represent enormous value — scientifically, commercially, and for patients. And they share a common foundation: the liver.
The liver, it turns out, is a forgiving first frontier. The early LNP designs needed only modest optimization to achieve hepatic delivery. But not every disease that stands to benefit from nucleic acid medicines originates in the liver. In fact, most don’t. Cancer, autoimmune disorders, neurological conditions, and cardiovascular disease involve cells and tissues that are far less accessible: T cells circulating in the blood, macrophages in inflamed tissue, neurons behind the blood-brain barrier.
If the first era of nucleic acid medicine was defined by what could be achieved by delivering to the liver, the next era will be defined by what becomes possible when delivery can go anywhere.