Lipid nanoparticles (LNPs) have revolutionized the delivery of genetic therapies, most famously enabling the deployment of mRNA vaccines at a global scale. However, despite their remarkable success, conventional LNPs remain largely confined to a single target organ: the liver. For the field of nanomedicine to expand its therapeutic horizons, a central challenge must be addressed. How can we achieve reliable extrahepatic delivery of lipid nanoparticles?
Why estrahepatic delivery matters
The ability to direct LNPs beyond the liver opens the door to treating a wide range of diseases, including solid tumors, pulmonary disorders, and immune-related conditions. The spleen, lungs, lymph nodes, and even specific immune cell populations are all promising targets for nucleic acid-based therapies – if we can deliver cargo with precision.
Yet, the innate preference of LNPs to accumulate in hepatocytes, driven by their composition and interactions with serum proteins like apolipoprotein E (ApoE), has long restricted therapeutic applications. Breaking this hepatic barrier requires a deep understanding of how LNP components influence biodistribution.
The power of lipid composition: our use of sphingomyelin
At DIVERSA, we have embraced an approach that rethinks LNP composition from the ground up. Central to our strategy is the incorporation of sphingomyelin, a lipid naturally present in biological membranes. Unlike traditional helper lipids such as DSPC, sphingomyelin contributes to increased membrane stability, fusion and endosomal scape behavior, which can significantly influence the pharmacokinetics and organ tropism of the nanoparticle.
Importantly, sphingomyelin can provide a potential route for re-directing LNPs away from hepatic uptake and toward other tissues. We have observed that SM-based LNPs exhibit distinct biodistribution profiles, offering a promising path to extrahepatic targeting.
Backed by science, a new study maps the path forward
A recent study published in Nature Communications (April 2025) provides compelling validation for this line of research. The authors conducted a systematic screening of LNP compositions, evaluating how specific lipids influence organ-selective delivery. Notably, the study identified sphingomyelin as one of the key lipids that enhances extrahepatic delivery, particularly to organs such as the spleen and lungs, by altering nanoparticle structure and serum protein interactions (Zhou et al., 2025).
This finding strongly supports our own formulation strategy at DIVERSA. By integrating sphingomyelin into our nanoparticle designs, we aim to intentionally steer biodistribution away from the liver and toward clinically relevant extrahepatic targets. The study reinforces a growing consensus in the field: extrahepatic delivery is a tunable feature enabled by rational lipid selection.
Where we are headed, organ-target nanomedicine
As the field moves forward, we envision a future where nanoparticles can be programmed not only to carry therapeutic payloads, but to seek out specific tissues with high precision. This could involve:
- Careful selection of lipids and biomaterials
- Pairing lipid optimization with ligand-based targeting,
- Leveraging machine learning to predict optimal compositions,
- Or developing hybrid systems that combine responsive or immunomodulatory lipids.
At DIVERSA, we are committed to advancing these frontiers through both in-house innovation and collaborative research. Extrahepatic delivery is no longer a distant goal; it’s an emerging reality powered by smart formulation design and mechanistic insight.
Interested in learning more about our sphingomyelin-based nanoplatform or exploring collaborative opportunities?
Visit www.diversatechnologies.com or send an email to info@diversatechnologies.com to explore our solutions.
References
Internal References
- Lipid nanoparticles: advancing your research, no matter which area you work in.
- How can nanotechnology boost gene therapy potential in rare disease?
- The difference between lipid nanoparticles and liposomes
- Innovations and challenges in Lipid Nanoparticles development
External References
- Cheng, M. H. Y., Zhang, Y., Fox, K., Leung, J., Strong, C., Kang, E., … & Cullis, P. R. (2025). Liposomal lipid nanoparticles for extrahepatic delivery of mRNA. Nature Communications, 16(1), 4135. doi.org/10.1038/s41467-025-58523-w
- Simonsen, J. B. (2024). Lipid nanoparticle-based strategies for extrahepatic delivery of nucleic acid therapies–challenges and opportunities. Journal of Controlled Release, 370, 763-772. doi.org/10.1016/j.jconrel.2024.04.022
