Nanodisc: Multifunctional Drug Carrier and Targeted Delivery System

What is Nanodisc ?

Nanodiscs are disc-shaped phospholipid bilayers self-assembled by phospholipids and membrane scaffold protein (MSP) particles, an artificial membrane scaffold protein similar to ApoA-1 protein. ApoA-1 is an important part of high-density lipoprotein (HDL) in the human body and plays an important role in the process of reverse cholesterol transport (RCT). ApoA-1 consists of 243 amino acid residues. After cutting off 43 amino acid residues at its N-terminus, a soft and tough MSP particle can be formed, which can be used to prepare nanodiscs.

The most common way to prepare nanodiscs is to add MSP particles to phospholipids containing detergents at an appropriate molar ratio, and then choose an appropriate method to remove the detergents. Finally, MSP particles will entrap liposomes to form a disc-shaped complex, namely nanodisks. Among them, the two most widely used MSP particles are MSP1D1 and MSP1EE3D1. MSP1D1 was used to form smaller nanodisks with a diameter of approximately 9.7 nm, while MSP1E3D1 formed larger nanodisks with a diameter of approximately 12.9 nm.

Fig.1 Illustrations of Nanodisc structures (Bayburt T. H., Sligar S. G. 2010).

Nanodiscs as Drug Carriers

According to statistics, about 40% of the newly discovered chemical drugs are fat-soluble drugs, and their low water solubility greatly limits their biological research progress. In the process of intravenous injection, it is often necessary to add a solubilizer to improve its utilization rate. However, this treatment method can easily lead to problems such as large injection doses and toxic side effects. The nanodisk simulates the biomembrane phospholipid bilayer structure, the hydrophilic head of the phospholipid molecule is exposed on the outside, the lipophilic long chain is located inside the nanodisc structure, and the loaded drug is wrapped in the middle of the internal lipophilic long chain. It has been proved that the nanodisc has a good loading capacity for lipophilic drugs.

At the same time, the drug preparations constructed by the nano drug delivery system are small in size and narrow in particle size distribution. After surface modification, target-specific positioning can be carried out to achieve targeted drug delivery, and it can also protect drug molecules, and improve stability and biocompatibility. In addition, it can combine imaging and treatment to realize the diagnosis and treatment of diseases. The application of chemotherapy in the treatment of tumor diseases has made great progress.

So far, nanodiscs as drug carriers have made great progress in applied research due to their special advantages, such as controlled drug release, targeting function, and high drug loading rate, but they are currently limited to animal models. It still needs further in-depth exploration and verification before it is expected to better play its advantages as a drug carrier in clinical use.

Nanodisc May Become An Ideal Platform for the Study of Membrane Protein Function

Membrane proteins not only serve as the scaffolding structure of the cell membrane but also play a key role in cellular processes such as signal transduction and material transport. However, due to its amphipathic nature, it is difficult to directly purify, and it is prone to problems such as intracellular toxicity, protein misfolding, and protein aggregation on the membrane surface during the overexpression process, which greatly limits the research on natural membrane proteins. Nanodisc technology is expected to be one of the powerful tools to solve these problems.

When nanodisc technology is combined with the purification process of membrane proteins, there are mainly two ways. Firstly, the membrane protein is purified by detergent or other traditional means to obtain a pure and single target membrane protein, and then the target protein is mixed with MSP particles at an appropriate molar ratio, and lipids are added to allow the target membrane protein to self-polymerize. In order to realize the expression of membrane proteins in the pseudo-membrane environment of nanodiscs. Second, directly introduce MSP particles into the membrane protein mixture, and at the same time add excess lipids to obtain a variety of nanodisc structures, some of which express target membrane proteins, and some of them interfere with the expression of the target membrane protein, then different nanodiscs are sorted and purified to achieve the purpose of leaving only the target membrane protein expression nanodisc is achieved.

As an artificially prepared membrane-like structure, nanodiscs provide a better platform for the research of membrane proteins that have been affected by structural instability and inconvenient aggregation for a long time. Its size is adjustable and can adapt to the expression of target membrane proteins of different sizes. It has the advantages of long half-life, strong stability, high solubility, and precise targeting in the membrane-mimetic environment, which has been widely used in the production and purification of membrane proteins, drug target research for receptor-ligand binding, and structural biology and other fields. At the same time, in the field of clinical medicine, nanodiscs have shown great potential in drug carriers, vaccine preparation, and the prevention and treatment of various diseases.

References

1. Bayburt T. H.; Sligar S. G. Membrane protein assembly into Nanodiscs. FEBS Letters. 2010, 584(9): 1721-1727.
2. Rouck J. E.; et al. Recent advances in nanodisc technology for membrane protein studies (2012–2017). et al. 2017, 591(14): 2057-2088.