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
The CDC buried a measles forecast that stressed the need for vaccinations
This story was originally published on ProPublica, a nonprofit newsroom that investigates abuses of power. Sign up to receive our biggest stories as soon as they’re published. ProPublica — Leaders at the Centers for Disease Control and Prevention [...]
Light-Driven Plasmonic Microrobots for Nanoparticle Manipulation
A recent study published in Nature Communications presents a new microrobotic platform designed to improve the precision and versatility of nanoparticle manipulation using light. Led by Jin Qin and colleagues, the research addresses limitations in traditional [...]
Cancer’s “Master Switch” Blocked for Good in Landmark Study
Researchers discovered peptides that permanently block a key cancer protein once thought untreatable, using a new screening method to test their effectiveness inside cells. For the first time, scientists have identified promising drug candidates [...]
AI self-cloning claims: A new frontier or a looming threat?
Chinese scientists claim that some AI models can replicate themselves and protect against shutdown. Has artificial intelligence crossed the so-called red line? Chinese researchers have published two reports on arXiv claiming that some artificial [...]
New Drug Turns Human Blood Into Mosquito-Killing Weapon
Nitisinone, a drug for rare diseases, kills mosquitoes when present in human blood and may become a new tool to fight malaria, offering longer-lasting, environmentally safer effects than ivermectin. Controlling mosquito populations is a [...]
DNA Microscopy Creates 3D Maps of Life From the Inside Out
What if you could take a picture of every gene inside a living organism—not with light, but with DNA itself? Scientists at the University of Chicago have pioneered a revolutionary imaging technique called volumetric DNA microscopy. It builds [...]
Scientists Just Captured the Stunning Process That Shapes Chromosomes
Scientists at EMBL have captured how human chromosomes fold into their signature rod shape during cell division, using a groundbreaking method called LoopTrace. By observing overlapping DNA loops forming in high resolution, they revealed that large [...]
Bird Flu Virus Is Mutating Fast – Scientists Say Our Vaccines May Not Be Enough
H5N1 influenza is evolving rapidly, weakening the effectiveness of existing antibodies and increasing its potential threat to humans. Scientists at UNC Charlotte and MIT used high-performance computational modeling to analyze thousands of viral protein-antibody interactions, revealing [...]
Revolutionary Cancer Vaccine Targets All Solid Tumors
The method triggers immune responses that inhibit melanoma, triple-negative breast cancer, lung carcinoma, and ovarian cancer. Cancer treatment vaccines have been in development since 2010, when the first was approved for prostate cancer, followed [...]
Scientists Uncover Hidden Protein Driving Autoimmune Attacks
Scientists have uncovered a critical piece of the puzzle in autoimmune diseases: a protein that helps release immune response molecules. By studying an ultra-rare condition, researchers identified ArfGAP2 as a key player in immune [...]
Mediterranean neutrino observatory sets new limits on quantum gravity
Quantum gravity is the missing link between general relativity and quantum mechanics, the yet-to-be-discovered key to a unified theory capable of explaining both the infinitely large and the infinitely small. The solution to this [...]
Challenging Previous Beliefs: Japanese Scientists Discover Hidden Protector of Heart
A Japanese research team found that the oxidized form of glutathione (GSSG) may protect heart tissue by modifying a key protein, potentially offering a novel therapeutic approach for ischemic heart failure. A new study [...]
Millions May Have Long COVID – So Why Can’t They Get Diagnosed?
Millions of people in England may be living with Long Covid without even realizing it. A large-scale analysis found that nearly 10% suspect they might have the condition but remain uncertain, often due to [...]
Researchers Reveal What Happens to Your Brain When You Don’t Get Enough Sleep
What if poor sleep was doing more than just making you tired? Researchers have discovered that disrupted sleep in older adults interferes with the brain’s ability to clean out waste, leading to memory problems [...]
How to prevent chronic inflammation from zombie-like cells that accumulate with age
In humans and other multicellular organisms, cells multiply. This defining feature allows embryos to grow into adulthood, and enables the healing of the many bumps, bruises and scrapes along the way. Certain factors can [...]
Breakthrough for long Covid patients who lost sense of smell
A breakthrough nasal surgery has restored the sense of smell for a dozen long Covid patients. Experts at University College London Hospitals NHS Foundation Trust successfully employed a technique typically used for correcting blocked nasal passages, [...]
