Nanodiscs are synthetic phospholipid particles with a distinct morphology and size that enhance their efficiency in drug delivery applications.1 First developed by Sligar et al. in the early 2000s, these model membrane systems measure around 10 nm in diameter with a thickness between 4.6 and 5.6 nm.2 Structurally, nanodiscs are similar to high-density lipoproteins.
In medical applications, nanotechnology advancements have positioned nanodiscs as valuable tools for diagnosing and treating various diseases. These disc-shaped particles can preserve membrane proteins in their functional state outside the cellular environment, making them valuable in biomedical applications.1
Nanodiscs stabilize fragile proteins, enhance drug delivery, and provide a structured bilayer surface, proving highly effective for studying cellular signaling complexes on membrane surfaces.1 Their versatility continues to support advancements in modern medicine.
Classification of Nanodiscs
Nanodiscs can be categorized based on the stabilizer used to maintain their structure.3
Membrane Scaffold Protein Nanodiscs
Membrane scaffold protein (MSP) nanodiscs use amphipathic membrane scaffold proteins as stabilizers. These scaffold proteins encircle a stable, discoidal phospholipid bilayer containing embedded transmembrane proteins, forming the nanodisc structure.
MSP is typically a truncated form of apolipoprotein A-I (apoA-I), a component of high-density lipoproteins. It wraps around a small segment of the phospholipid bilayer to create the disc-shaped nanodisc.3
MSP provides a hydrophobic surface for lipid tails and a hydrophilic outer surface, making nanodiscs highly soluble in water. During assembly, excess detergent is used and later removed with bio-beads, allowing membrane proteins to stay in solution without detergents.
These nanodiscs are well-suited for studying membrane proteins in both prokaryotic and eukaryotic systems, including key structures like transporters, ion channels, and G protein-coupled receptors (GPCRs).4
Saposin nanodiscs
The saposin protein family consists of four members, saposin A–D, each with a molecular weight of around 10 kDa. Saposin A is most commonly used for assembling saposin nanodiscs. Frauenfeld et al. (2016) demonstrated the use of saposin proteins as scaffolds to reconstitute various membrane proteins within a phospholipid environment.5
Saposin nanodiscs self-assemble from saposin proteins, phospholipids, and membrane proteins into a stable structure that is adaptable to various membrane protein sizes without requiring scaffold construction or lipid ratio adjustments.3 Although a recent development, they are widely applied in structure-based techniques like NMR and cryo-EM, providing distinct advantages for both methods.
For example, in a solution-based NMR study, three membrane proteins were successfully incorporated into saposin nanodiscs: bacterial outer membrane protein X (OmpX), sensory receptor rhodopsin II (pSRII), and the β1-adrenergic receptor (β1AR).6
Copolymer Nanodiscs
Copolymer nanodiscs extract membrane proteins directly from cell membranes, preserving their native state and endogenous phospholipids. Synthetic polymers encapsulate the proteins into nanosized discs, stabilizing a portion of the native membrane. These nanodiscs use the cell’s natural phospholipids, with the polymer acting as both solubilizer and stabilizer, removing the need for additional detergents.3
Synthetic copolymers like styrene-maleic acid (SMA), diisobutylene maleic acid (DIBMA), and polymethacrylate (PMA) are used to stabilize nanodiscs, maintaining the lipid bilayer in aqueous solutions. These non-protein polymers self-assemble into stable structures and offer higher purity than MSP nanodiscs. They are widely used in membrane protein research, drug delivery, and biosensor applications.3
SMA nanodiscs have been successfully employed to purify and study integral membrane proteins from bacterial and eukaryotic systems. Once reconstituted into SMA nanodiscs, these proteins are well-suited for high-resolution structural analysis via cryo-EM, as well as for receptor-ligand binding assays and functional activity studies.7
Applications of Nanodiscs in Medicine
Drug Delivery
Nanodiscs offer an effective platform for enhancing drug delivery systems, particularly for drugs with low water solubility. Their lipid bilayer structure can encapsulate hydrophobic drugs, protecting them from premature degradation while enhancing their bioavailability.3
Chen et al. designed lipid nanodiscs functionalized with cyclic RGD peptide (cRGD) on either the edges or planes, creating two distinct anisotropic targeting nanocarriers (E-cRGD-NDs and P-cRGD-NDs) for siRNA delivery.8 E-cRGD-NDs demonstrated significant advantages in siRNA loading, cellular uptake, gene silencing efficiency, protein expression, and in vivo performance.
In a 2023 study, Yu et al. developed antibodies targeting matrix protein 2 (M2) of the influenza A virus. M2 (1-46) was incorporated into nanodiscs to form a membrane-embedded tetrameric structure, closely resembling its natural physiological state within the influenza virus envelope.9
Companies like Cube Biotech are actively developing nanodisc-based drug delivery systems that can be customized for different therapeutic needs. Its lipid-based nanodiscs offer a flexible platform for encapsulating and delivering various pharmaceuticals, including biologics and small-molecule drugs.
Vaccine Development
Nanodiscs have emerged as promising platforms for developing personalized tumor immunotherapy and vaccines against infectious diseases. They can be loaded with antigenic peptides or tumor markers, preserving the structure and activity of membrane proteins, which makes them highly immunogenic.1
Aldehyde dehydrogenase (ALDH) has been extensively used as a marker for isolating cancer stem cells (CSCs). These cells are characterized by high proliferation rates and play a role in tumor metastasis and recurrence.10 ALDH-positive CSCs have been identified in over 20 different tumor types.1
In a 2020 study, James J. Moon’s research group developed synthetic nanodiscs for vaccines targeting ALDHhigh CSCs. These nanodiscs improve antigen delivery to lymph nodes and trigger strong ALDH-specific T-cell responses, offering a promising new approach for cancer immunotherapy focused on CSCs.11
Diagnostic Tools
Nanodiscs offer considerable potential for creating advanced diagnostic tools. Their ability to stabilize membrane proteins in their native conformation makes them excellent tools for studying protein-protein interactions, enzymatic functions, and other cellular processes.12
NMR has long been used to gather structural information on soluble proteins. Rienstra and colleagues were the first to report solid-state NMR (ssNMR) spectra of nanodiscs, confirming that membrane scaffold proteins are organized in a “belt” configuration.13
Recently, there has been substantial growth in the use of both solution and ssNMR methods with nanodiscs, providing critical insights into the structure and function of membrane proteins. For instance, the complete three-dimensional structure of OmpX in nanodiscs, obtained through solution NMR, highlighted the ability to detect subtle conformational differences in a native bilayer environment.14
Conclusion
Nanodiscs represent a transformative innovation in medicine, with applications spanning protein stabilization, drug delivery, vaccine development, and diagnostics. Their ability to mimic natural cell membranes while remaining stable in various environments allows for broad applications in both research and clinical contexts.
Looking ahead, the future of nanodiscs in healthcare is strong. Continued research into polymer-based and MSP nanodiscs could lead to more robust and customizable platforms for therapeutic and diagnostic use.
As more companies and research institutions explore these applications, nanodiscs are likely to support more precise, effective, and personalized treatments in modern medicine.
References and Further Reading
1. Mu, Q., Deng, H., An, X., Liu, G. Liu, C. (2024). Designing nanodiscs as versatile platforms for on-demand therapy. Nanoscale. https://pubs.rsc.org/en/content/articlelanding/2024/nr/d3nr05457h
2. Nath, A., Atkins, WM. Sligar, SG. (2007). Applications of Phospholipid Bilayer Nanodiscs in the Study of Membranes and Membrane Proteins. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/17263563/
3. Dong, Y., Tang, H., Dai, H., Zhao, H. Wang, J. (2024). The application of nanodiscs in membrane protein drug discovery & development and drug delivery. Front. Chem. https://pmc.ncbi.nlm.nih.gov/articles/PMC11445163/
4. Zhang, M. et al. (2021). Cryo-EM structure of an activated GPCR–G protein complex in lipid nanodiscs. Nat. Struct. Mol. Biol. https://pubmed.ncbi.nlm.nih.gov/33633398/
5. Frauenfeld, J. et al. (2016). A saposin-lipoprotein nanoparticle system for membrane proteins. Nat. Methods. https://pubmed.ncbi.nlm.nih.gov/26950744/
6. Chien, C.-T. H. et al. (2017). An adaptable phospholipid membrane mimetic system for solution NMR studies of membrane proteins. J. Am. Chem. Soc. https://pubmed.ncbi.nlm.nih.gov/28990386/
7. Swainsbury, DJK. et al. (2023). Cryo-EM structure of the four-subunit Rhodobacter sphaeroides cytochrome bc 1 complex in styrene maleic acid nanodiscs. Proc. Natl. Acad. Sci. https://www.pnas.org/doi/10.1073/pnas.2217922120
8. Chen, X., Zhou, Y., Zhao, Y. Tang, W. (2023). Targeted degradation of extracellular secreted and membrane proteins. Trends Pharmacol. Sci. https://pubmed.ncbi.nlm.nih.gov/37758536/
9. Yu, C. et al. (2023). Screening and characterization of inhibitory vNAR targeting nanodisc-assembled influenza M2 proteins. Iscience. https://pubmed.ncbi.nlm.nih.gov/36570769/
10. Marcato, P., Dean, CA., Giacomantonio, CA. Lee, PWK. (2011). Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell cycle. https://pubmed.ncbi.nlm.nih.gov/21552008/
11. Hassani Najafabadi, A. et al. (2020). Cancer immunotherapy via targeting cancer stem cells using vaccine nanodiscs. Nano Lett. https://pmc.ncbi.nlm.nih.gov/articles/PMC7572838/
12. Denisov, IG. Sligar, SG. (2017). Nanodiscs in membrane biochemistry and biophysics. Chem. Rev. https://pubmed.ncbi.nlm.nih.gov/28177242/
13. Li, Y., Kijac, AZ., Sligar, SG., Rienstra, CM. (2006). Structural analysis of nanoscale self-assembled discoidal lipid bilayers by solid-state NMR spectroscopy. Biophys. J. https://pubmed.ncbi.nlm.nih.gov/16905610/
14. Hagn, F., Wagner, G. (2015). Structure refinement and membrane positioning of selectively labeled OmpX in phospholipid nanodiscs. J. Biomol. NMR. https://pubmed.ncbi.nlm.nih.gov/25430058/
News
Our books are available worldwide!
Online Sellers other than Amazon, Routledge, and IOPP Indigo Global Health Care Equivalency in the Age of Nanotechnology, Nanomedicine and Artifcial Intelligence Global Health Care Equivalency In The Age Of Nanotechnology, Nanomedicine And Artificial [...]
After only a short training, people in a coma managed to send targeted signals
Researchers have succeeded in communicating with brain-injured patients who are unconscious. They see enormous potential in this for future treatments. Patients who lie motionless in bed after a severe brain injury and do not [...]
MIT Scientists Reprogram Immune Cells Inside the Body To Destroy Cancer
Natural killer cells reprogrammed inside mice eliminated lymphoma tumors and helped damaged livers heal, though whether this approach could help people with cancer or autoimmune disease remains unknown. To make a cancer treatment from [...]
Melanoma mRNA Vaccine Shows Promise in Preventing Disease Recurrence
Key takeaways: Phase 3 trial finds personalized intismeran plus pembrolizumab may better prevent high-risk melanoma recurrence after surgery The trial enrolled 1,137 patients and builds on phase 2 results showing about half the recurrence [...]
Scientists Discover a Powerful New Weapon Against a Dangerous Gut Infection
The promise of an experimental treatment for C. difficile gut infections lies partly in the bacteria it leaves alive, according to early laboratory and mouse research. Broad-spectrum antibiotics can disrupt the gut’s microbial community, [...]
Your Bones May Hold a Hidden Clue to Blood Cancer Survival
For people with blood cancers called myelodysplastic syndromes, osteoporosis may hold an overlooked clue to survival, a three-year observational study suggests. In blood cancers that develop in the bone marrow, an important clue to [...]
Researchers Discover What Reading for Pleasure May Be Doing to Your Brain
Reading for pleasure may offer surprising benefits for the brain, with research linking the habit to better mental health, stronger cognitive abilities, and a lower risk of dementia. Reading for pleasure may do far [...]
Scientists Discover a Hidden Trigger That Keeps Inflammation Alive
Inflammation persists after proteins detach from immune receptors, revealing a potential target for autoimmune treatments. Since a Nobel Prize-winning discovery in the 1990s identified molecules called Toll-like Receptors as the guardians of the human [...]
A Virus Gives Itself Away the Moment It Attacks
Researchers have found the trigger behind a powerful bacterial defense against viruses. Viruses that prey on bacteria could become an increasingly important tool for treating bacterial infections, particularly as antibiotic resistance makes some infections [...]
Scientists Discover Aspirin May Slash Dementia Risk by 70% – but Only for Certain People
Aspirin was linked to a sharply lower dementia risk in some older adults, and their genes may hold the clue. A Monash University analysis found that older adults with a particular genetic profile had [...]
Inflammation May Awaken Dormant Cancer Cells Years After Treatment
The body’s response to inflammation may disturb cancer cells that have been lying silent for years, giving them an opportunity to grow again. Researchers at the Francis Crick Institute have found that gut inflammation [...]
Where do nanoparticles go once they enter the body?
New international best practice guidance, co-written at ANSTO, sets out how to measure where nanoparticles like titanium dioxide end up in the body and how long they remain. The guidance has been shared by [...]
Long-Acting HIV Shots Could Solve a Major Treatment Challenge for Young People
A major African trial suggests that changing how HIV treatment is delivered could significantly improve viral suppression in adolescents. Young people with HIV were more likely to keep the virus suppressed when they received [...]
WHO Factsheets – The top 10 causes of death
In 2023, the 10 leading causes of death accounted for 33 million deaths, or 54% of the total 61 million deaths worldwide. The top global causes of death, in order of total number of lives lost, [...]
Aging Cells May Be Hiding From the Immune System – Scientists Think They Know How
Your immune system is supposed to clear out damaged cells. Researchers may have found how some of them hide and linger as the body ages. Researchers led by Cedars-Sinai Health Sciences University have identified [...]
Your Voice May Reveal How Fast Your Brain Is Aging
Researchers have developed a machine-learning “speech clock” that estimates age from subtle patterns in how people speak and what they say. It is possible that people’s voices may contain certain signals of aging that [...]
