Understanding Lipid Particle Shapes: The Key to Effective Drug Delivery

Lipid particle morphologies are diverse, shaped by the structural variety of the lipids themselves. This diversity results in distinct forms such as lipid nanoparticles (LNPs), micelles, and liposomes, each with unique characteristics and applications. LNPs are solid-core particles used primarily for drug delivery, micelles are self-assembled particles that vary based on their environment, and liposomes are versatile vesicles formed by lipid bilayers, available in different sizes and types. Understanding these different morphologies, from small unilamellar vesicles (SUVs) to complex multi-vesicular structures, is essential for optimizing their use in research and pharmaceutical applications. Keep reading to learn more about the different lipid particle morphologies!

Lipids are a large class of water-insoluble compounds that covers a wide range of molecular structures. The variety lipids offer in their structure translates to different particle morphologies.

LNPs

LNPs, short for lipid nanoparticles, is the term currently used to describe solid-core lipid vesicles encapsulating negatively charged nucleic acid cargo. LNPs can be composed of many different lipid classes and structures, but always utilize a cationic lipid to allow for condensation of anionic nucleic acids, thereby forming the solid core particles. LNPs are usually around 80nm in size.

Micelles

Micelles are single layer particles with hydrophilic lipid heads in contact with aqueous buffer while the hydrophobic lipid tails are oriented inward to sequester small hydrophobic cargo. Conversely, inverted (or reverse) micelles are formed in oils where the hydrophobic tails orient outward facing the oil to protect the hydrophilic heads which contain the water droplets. Micelles are small in size, typically less than 30nm while inverted micelles are larger, sometimes around 200nm. Micelles self-assemble into their final formation, but energy may be required to decrease particle size, especially for water in oil emulsions.

Liposomes

Liposomes can come in a variety of sizes and styles. All liposomes are composed of lamella, or layers. Every lamella of a liposome is made of a lipid bilayer. The bilayer consists of two rows of lipids, fatty acid tails together, with hydrophobic heads in contact with the interior and exterior aqueous phases. The number and orientation of those lamella are what allows us to categorize liposomes differently.

SUVs

Small unilamellar vesicles, or SUVs, are what we think of as traditional liposomes. These have a single bilayer with an aqueous core and are less than 200nm. SUVs can be formed using ethanol injection or from thin-film hydration method, employing sonication, high pressure extrusion or homogenization to obtain smaller particle sizes. These two production techniques are distinctly different in how the particle is formed, but in both cases, the lipids self assemble when placed in contact with an aqueous system.

LUVs

Large unilamellar vesicles, or LUVs, are similar to SUVs, but are much larger, from 200nm to 1um. These can be prepared by a variety of methods including extrusion, reverse evaporation, and ethanol injection. LUVs are commonly used for studying protein fusion.

GUVs

Then, there are GUVs or giant unilamellar vesicles, which are structurally similar to SUVs and LUVs but are 1-30µm in size. GUVs use lipids with low curvature. Historically GUVs could be produced through thin film hydration with the most gentle of mixing, but this is not reproducible as the mixing techniques are hard to control. The most common method to produce GUVs now uses electroformation¹, but other techniques are also possible: gel assisted swelling², detergent-mediated reconstitution³, or droplet transfer method⁴. Click here for our vesicle preparation protocol!

While different methods are employed to produce the various lipid vesicle morphologies, it is important to consider the lipid composition as well. High curvature lipids should be used for micelles and SUVs, but reduced or avoided altogether for LUVs and GUVs.

SUVs, LUVs, and GUVs are all single lamella particles. But, vesicles consisting of more than one bilayer also exist. Both multi-vesicular liposomes (MVLs) and multi-lamellar vesicles (MLVs) are also used. MLVs are contain multiple concentric bilayers with aqueous pockets in between. MVLs is basically a giant vesicle composed of mini liposomes. Both of these types of systems are used in drug products for delivering high quantities of API, or controlled release of API.

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1. Angelova, M. I. & Dimitrov, D. S. Liposome electroformation. Faraday Discuss. 81, 303–311 (1986).
2. Weinberger, A. et al. Gel-assisted formation of giant unilamellar vesicles. Biophys. J. 105, 154–164 (2013).
3. Dezi, M., Cicco, A. D., Bassereau, P. & Lévy, D. Detergent-mediated incorporation of transmembrane proteins in giant unilamellar vesicles with controlled physiological contents. Proc. Natl. Acad. Sci. USA 110, 7276–7281 (2013).
4. Yanagisawa, M., Iwamoto, M., Kato, A., Yoshikawa, K. & Oiki, S. Oriented reconstitution of a membrane protein in a giant unilamellar vesicle: Experimental verification with the potassium channel KcsA. J. Am. Chem. Soc. 133, 11774–11779 (2011).