Archaeal tetraether lipids for LNP and liposome delivery

Through its collaboration with NovoArc, Avanti Research™ is bringing archaeal tetraether lipids into the spotlight as a powerful alternative to traditional lipid systems used in drug delivery. Inspired by the extremely resilient archaeal membrane structures found in extremophiles, these archaeal lipids are engineered to overcome many of the stability problems tied to standard phospholipid formulations.

Unlike conventional membrane lipid systems built around ester bonds, these tetraether lipid structures rely on durable ether bonds and membrane-spanning molecular architecture that can tolerate harsh environmental factors, including high temperatures, extreme pH conditions, and oxidative stress. That added chemical stability creates new opportunities for researchers developing lipid nanoparticles (LNPs), liposomes, and other delivery platforms for nucleic acids, oral therapeutics, and injectable formulations.

The result is a more adaptable formulation toolkit: PEG-free stealth behavior, stronger gastrointestinal survival, and even room-temperature-stable lyophilized systems that may reduce or eliminate cold-chain requirements.

What are archaeal tetraether lipids?

Most modern liposomal and LNP systems are constructed from typical phospholipids containing ester-linked alkyl chains arranged into a membrane bilayer. Those systems work well in many applications, but ester bonds remain vulnerable to hydrolysis, oxidation, and acid degradation. Over time, that instability can compromise the cell membrane structure, shorten shelf life, and reduce performance during transport or exposure to demanding biological environments such as the gastrointestinal tract.

Archaeal tetraether lipids follow a very different biosynthetic pathway. Found naturally in thermoacidophilic archaea such as Sulfolobus acidocaldarius, these complex lipids replace ester linkages with chemically inert ether linkages. Their membrane-spanning structure is formed by two C40 isoprenoid chains, connected across the full width of the archaeal membrane, resulting in a dialkyl glycerol tetraether configuration rather than a traditional bilayer arrangement.

This glycerol tetraether framework, often referred to as glycerol dialkyl glycerol tetraether (GDGT) or caldarchaeol, forms membranes with a monolayer-like structure, exhibiting remarkably low proton permeability and strong resistance to degradation. In some molecular structures, cyclopentane rings or even a cyclohexane ring further reinforce rigidity and thermal resilience across a broad temperature range.

These GDGT membrane lipids, sometimes classified among archaeol lipids or macrocyclic archaeol derivatives, form the structural foundation of archaeosomes: lipid vesicles built from archaeal lipid substrate materials that have attracted growing attention in microbial ecology, organic geochemistry, and advanced therapeutic delivery research over the last two decades.

Why tetraether lipids for drug delivery?

Researchers continue to explore tetraether lipid systems because they address several long-standing limitations associated with conventional bacterial lipids and phospholipid delivery platforms.

• Extreme stability: The ether-linked molecular architecture of archaeal membrane lipids provides exceptional durability under conditions that typically destabilize conventional membrane lipid systems. Their resistance to hydrolysis, oxidation, and thermal stress makes them especially useful for formulations exposed to potent oxidant conditions, high pH values, or elevated growth temperature environments.
• Cold-chain relief: Lyophilized archaeal lipid formulations have demonstrated impressive long-term stability at room temperature. In preclinical work, archaeosomal systems maintained >95% structural integrity after six months of storage without requiring ultra-cold handling. That kind of performance could significantly simplify global distribution logistics for temp-sensitive therapeutics.
• Gastrointestinal survival: Conventional liposomes often struggle to survive exposure to gastric acid, bile salts, and digestive enzymes. Archaeal tetraether lipids show much stronger retention in simulated GI conditions, helping preserve sensitive therapeutic cargo during transit through the digestive tract.
• PEG-free stealth behavior: Repeated PEG exposure has raised concerns surrounding anti-PEG antibodies and accelerated blood clearance. GDGT-containing liposomes have demonstrated circulation profiles comparable to those of PEGylated systems without PEG, offering an alternative route for repeat-dose mRNA therapies.
• Enhanced cellular uptake: Studies with colonic cell lines showed a 37% increase in cellular uptake and a 6x increase in endocytosis when archaeal lipid formulations were used instead of standard phospholipid systems.

Applications

Oral delivery of injectable-only drugs

One of the most compelling advantages of GDGT-containing systems is their ability to protect therapeutic cargo throughout the gastrointestinal tract. Because these tetraether lipid formulations resist breakdown from acid and bile exposure, they may help convert therapies previously limited to injection into orally available options.

In preclinical studies, adding glycerol dialkyl glycerol tetraether lipids to liposomal vancomycin formulations increased oral bioavailability by ~9x compared to the free drug. Similar improvements have also been observed with CBD formulations.

Oral mRNA therapeutics

The same structural advantages that protect small molecules also support nucleic acid delivery. Researchers evaluating oral mRNA systems found that incorporating GDGT membrane lipids into standard LNP formulations increased oral mRNA bioavailability by ~11x in Wistar rat models.

Sustained protein expression observed during these studies points to archaeal tetraether lipids as a potentially important platform for future oral mRNA and saRNA therapeutics.

PEG-free stealth formulations

PEGylation remains widely used to prolong circulation time in intravenous delivery systems, but concerns about repeat exposure continue to grow. Anti-PEG immune responses and accelerated clearance have become especially relevant for recurring mRNA treatment regimens.

Preclinical pharmacokinetic studies involving GDGT-containing IV liposomes demonstrated circulation times comparable to those of PEGylated formulations without PEG incorporation. By leveraging the intrinsic properties of archaeal membrane structures, these formulations may offer a more durable, long-term strategy for stealth delivery applications.

Technical data highlights

Preclinical studies involving NovoArc archaeal lipid formulations have produced several notable findings:

• Storage stability: Lyophilized archaeosomal formulations retained more than 95% integrity after six months at room temperature.
• Oral bioavailability: Approximately 9x improvement for oral vancomycin delivery and roughly 11x improvement for oral mRNA delivery in Wistar rat models.
• Cellular uptake: A 37% increase in uptake and a 6x increase in endocytosis by colonic cell lines compared to standard phospholipid formulations.
• PEG-free stealth: GDGT-containing IV liposomes demonstrated circulation times similar to PEGylated systems.

View the full technical data, including methodology and performance charts, on our blog Avanti Research and NovoArc bring archaeal lipids to LNPs.

Avanti Research™ x NovoArc

The collaboration between Avanti Research™ and NovoArc brings advanced archaeal lipid technology directly into pharmaceutical and academic research settings.

Based in Vienna, NovoArc specializes in the development and production of archaeal ether lipids derived from thermoacidophilic archaea, including Sulfolobus acidocaldarius. Avanti Research™ supports manufacturing, structural characterization, and distribution efforts while maintaining the quality standards required for formulation development and mechanistic studies.

Together, the collaboration expands access to a new generation of membrane lipid building blocks—materials designed to move beyond the traditional lipid divide between conventional bacterial lipids and archaeal membrane systems. For researchers exploring more resilient, versatile, and stable delivery platforms, archaeal tetraether lipids offer a viable path forward.

References

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Jia, Y., Li, J., Wang, S. et al. (2022). Archaeosomes: Current applications and future prospects in drug delivery. Journal of Drug Delivery Science and Technology, 75, 103699.

‌Lie, G., Garcia, A. A., Fluke, K. A., Anderson, H. R., Davidson, S. C., Welander, P. V., & Santangelo, T. J. (2024). Tetraether archaeal lipids promote long‐term survival in extreme conditions. Molecular Microbiology, 121(5), 882–894. https://doi.org/10.1111/mmi.15240
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Romero, E.L. & Morilla, M.J. (2023). Archaeal lipids in the delivery of therapeutic agents. Expert Opinion on Drug Delivery, 20(1), 1–16.

Sedlmayr, V. L., Schobesberger, S., Spitz, S., Ertl, P., Wurm, D. J., Quehenberger, J., & Spadiut, O. (2024). Archaeal ether lipids improve internalization and transfection with mRNA lipid nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics, 197, 114213. https://doi.org/10.1016/j.ejpb.2024.114213

Sedlmayr, V. L., Schobesberger, S., Spitz, S., Ertl, P., Wurm, D. J., Quehenberger, J., & Spadiut, O. (2024). Archaeal ether lipids improve internalization and transfection with mRNA lipid nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics: official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V., 197, 114213. https://doi.org/10.1016/j.ejpb.2024.114213

Sedlmayr, V., Meid, A. D., Mühlberg, E., Böhmann, M. B., & Uhl, P. (2026). Beyond PEGylation: Archaeal Lipids for Long‐Circulating Liposomes. Advanced NanoBioMed Research. https://doi.org/10.1002/anbr.202500232
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Vidakovic, I., Kornmueller, K., Fiedler, D., Khinast, J., Fröhlich, E., Leitinger, G., Horn, C., Quehenberger, J., Spadiut, O., & Prassl, R. (2024). Archaeosomes for Oral Drug Delivery: From Continuous Microfluidics Production to Powdered Formulations. Pharmaceutics, 16(6), 694. https://doi.org/10.3390/pharmaceutics16060694
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Zeng, Z., Chen, H., Yang, H., Chen, Y., Yang, W., Feng, X., Pei, H., & Welander, P. V. (2022). Identification of a protein responsible for the synthesis of archaeal membrane-spanning GDGT lipids. Nature Communications, 13(1), 1545. https://doi.org/10.1038/s41467-022-29264-x