You Made the RNA.
Now How Do You Deliver It to the Cytoplasm?
For mRNA and siRNA therapeutics, producing high-quality nucleic acid is only part of the challenge. The cargo must also be protected, taken up by the appropriate cells and released efficiently into the cytoplasm. Ionizable lipids are central to this LNP delivery process.
Why Do Nucleic Acids Need LNPs?
Naked mRNA and siRNA face challenges including extracellular degradation and inefficient passage across cellular membranes.
Lipid nanoparticles can encapsulate nucleic-acid cargo, protect it during delivery and facilitate intracellular release.
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LNP Encapsulation
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Cellular Uptake
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Endosome
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Endosomal Escape
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Cytoplasmic Release
Why Ionizable Lipids Matter
An LNP formulation typically combines an ionizable lipid with helper phospholipids, cholesterol and PEG lipids.
The ionizable lipid plays a particularly important role in nucleic-acid encapsulation and intracellular delivery.
Ionizable lipids can remain relatively neutral under physiological conditions while becoming protonated in acidic endosomal environments, supporting membrane interactions and endosomal escape.
A Dual-Responsive Ionizable Lipid Design
NOF's COATSOME® SS Series incorporates two structural motifs designed to respond to different intracellular environments.
Responds to acidic endosomal/lysosomal environments and supports membrane destabilization.
2. Disulfide bond
Can be cleaved under the reducing environment of the cytoplasm.
This dual-responsive design is intended to combine efficient intracellular delivery with improved biodegradability.
Delivery and Degradation Need Different Properties
An LNP needs sufficient stability to protect its cargo during delivery, but persistence after cargo release is not necessarily desirable.
Biodegradable ionizable-lipid designs can help balance these competing requirements.
The SS Series uses intracellularly responsive structures to support nucleic-acid delivery while promoting lipid degradation after delivery.
Cargo and Destination Both Matter
LNP development is not simply a search for the formulation with the highest in-vitro transfection signal.
The desired biodistribution depends on the therapeutic application. NOF reports controlled targeting approaches involving the liver, spleen and lymph nodes, with its broader platform also addressing immune-cell delivery.
The optimal formulation therefore depends on both what is being delivered and where it needs to go.
Nucleic-Acid Applications
The COATSOME® SS platform supports encapsulation and delivery applications involving:
✓ mRNA
✓ siRNA
✓ pDNA
✓ Gene-editing payloads
Applications described by NOF include gene editing, vaccines and immune-disease programs.
An LNP Is a Formulation, Not a Single Lipid
Ionizable-lipid selection is important, but final LNP performance emerges from the complete formulation.
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Helper phospholipid
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Cholesterol
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PEG lipid
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Lipid ratio
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Particle size / PDI
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Encapsulation efficiency
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Cargo and target tissue
Each variable can influence stability, biodistribution and intracellular delivery.
Questions to Ask During LNP Development
✓ What cargo are you delivering — mRNA, siRNA or pDNA?
✓ Which tissue or cell population is the target?
✓ What encapsulation efficiency is required?
✓ Are particle size and PDI appropriate?
✓ Is endosomal escape efficient?
✓ What is the cytotoxicity/inflammatory profile?
✓ Does performance survive freeze-thaw cycles?
✓ Is frozen or lyophilized storage required?
✓ Can the formulation and lipid supply scale toward clinical development?
Developing an mRNA, siRNA or LNP Program?
Dana Bioscience can help source materials for nucleic-acid delivery including
ionizable lipids, phospholipids, PEG lipids and LNP formulation materials.
Share your cargo, target tissue or cell type, current formulation and development stage,
and we can help evaluate suitable materials, including NOF COATSOME® SS Series options.