NTU team develops ‘trojan horse’ drug delivery system

Scientists from NTU (Nanyang Technological University) Singapore have developed a new method of drug delivery using protein-based microdroplets.

drug delivery method
Image Credit: NTU Singapore

The discovery promises to be faster, safer, more effective and better suited for gene therapy, cancer treatment and vaccine delivery – including mRNA-based vaccines such as those used for Covid-19 vaccinations.

The microdroplets, which are made up of small proteins called peptides, can encase large biomacromolecules that carry drugs within them. In doing so, they allow these biological molecules to enter the cells, something the molecules cannot do on their own.

Biomacromolecules are large biological molecules such as nucleic acids (DNA, mRNA), proteins and carbohydrates. They can carry large quantities of drugs, are non-toxic, can target specific sites, and do not trigger the body’s immune response, making them preferable to synthetic carriers currently used in drug delivery.

However, their large size and inability to cross the cell membrane have prevented them from widespread clinical use.

Led by Professor Ali Miserez of NTU’s School of Materials Science & Engineering and School of Biological Sciences, the team’s method of first encapsulating biomacromolecules in protein-based microdroplets proved reliable and effective in getting them into cells.


Researchers said they synthesized a peptide derived from squid beak to form the microdroplet because of its biological origin, high efficiency in storing molecules and low toxicity. They were then able to capture the biomacromolecules within them through liquid-liquid phase separation (LLPS).

Just as oil and water can mix and yet be easily separated into two liquids, the LLPS process forms what is known as a coacervate that can merge into the cell membrane.

“Supposedly, the liquid-like properties of coacervates achieved through the liquid-liquid phase separation process are critical to their ability to cross the cell membrane, although the precise mechanism of entry is still unclear and currently under investigation,” said the paper’s lead author, NTU PhD student Yue Sun.

The discovery enables biomacromolecules to avoid endocytosis – the process by which cells allow foreign substances to enter by surrounding them with a protective membrane. Traditional drug delivery methods cannot penetrate the cell membrane without first being captured by the cell and wrapped in a ‘bubble’ of cell membrane or endosome.

Therefore, these types of drug packages must also be coded with further instructions to “escape” the endosome to deliver the drugs efficiently.

According to researchers, their coacervates can smoothly cross the cell membrane without causing endocytosis. Once in the cell, the carrier droplets disintegrate and the biomacromolecules are released.

“You can think of these droplets as molecular ‘Trojan horses’: they trick the cells into letting them in, and once they’re in, they deliver the biomacromolecular ‘soldiers’ that target the disease,” said Prof. Miserez .

The team said they have successfully delivered fluorescent proteins, which are often used to demonstrate the efficiency of drug carriers, as well as the protein drug saporin through this method. They found that the cell entry process had a 99 percent success rate compared to the 50-70 percent of current commercially available carriers.

“Our peptide droplets can work as a universal delivery system without the need for individual adjustments. One delivery system for a whole range of proteins of different sizes, from large to small, and which can transport both positively and negatively charged proteins, is very attractive,” said Miserez.

Findings were published in natural chemistry The team has filed for two patents based on its research and is working to commercialize the drug delivery platform.

Abhishek Maheswari
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