Scientists from Nanyang Technological University have developed a novel method of delivering drugs into human cells using large biological molecules, by first encasing them in a protein-based microdroplet.
This 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 currently used for Covid-19 vaccinations by Pfizer and Moderna.
These microdroplets, made up of small proteins named peptides, can encase large biomacromolecules that carry drugs inside them. In doing so, they allow these biological molecules to enter cells, something the molecules cannot do by themselves.
Biomacromolecules are large biological molecules such as nucleic acids (DNA, mRNA), proteins and carbohydrates. They are of great research interest as drug carriers, as they can carry a large amount of drugs, are nontoxic, able to target specific sites, and do not trigger the body’s immune response. This makes them preferable and advantageous over synthetic carriers currently used in the market.
However, their large size and inability to pass through the cell membrane have held them back from widespread clinical use.
Now, the NTU research team, led by Professor Ali Miserez from the School of Materials Science & Engineering and the School of Biological Sciences, showed in lab experiments that their method of first encasing drug-carrying biomacromolecules in protein-based microdroplets lets them reliably and effectively enter cells, overcoming the main challenge of cell entry.
“Biomacromolecules are promising therapeutic prospects for the treatment of various diseases as they have high potency, specificity, and are very safe,” said Prof Miserez. “Despite this broad potential, biomacromolecules suffer from a major drawback: they are impermeable to the cell membrane and thus cannot penetrate the cell by themselves. They need help, which is where our platform comes into place.”
The findings were published in the scientific journal Nature Chemistry in February. The study was funded by a Ministry of Education Tier 3 grant.
The research team has filed two patents based on their published study and are working to commercialise their drug delivery platform method through NTUitive, the University’s innovation and enterprise company.
The development of the team’s novel drug delivery system is aligned with NTU’s commitment to innovation in its recently announced 2025 strategic plan, which aims to translate research into products and outcomes that enhance the quality of life.
The researchers synthesised a peptide derived from squid beak to form the microdroplet due to its biological origin, high efficiency in storing molecules, and low toxicity. They were then able to entrap biomacromolecules inside it through a process called liquid-liquid phase separation (LLPS).
This LLPS process, similar to how oil and water can mix together yet easily separate into two distinct liquids, forms what is known as a coacervate.
This coacervate is able to merge into the cell membrane, although the exact reason why is currently unknown. “Presumably, the liquid-like properties of coacervates achieved via the liquid-liquid phase separation process is critical in their ability to cross the cell membrane, although the precise entry mechanism is still unclear and currently under investigation,” said the paper’s first author, NTU PhD student Yue Sun.
Crucially, this discovery allows biomacromolecules to avoid endocytosis — the process where cells allow foreign substances to enter by surrounding it with a protective membrane.
Traditional drug delivery methods cannot cross into the cell membrane without first being caught by the cell and wrapped within a ‘bubble’ of cell membrane, or endosome. Therefore, these types of drug packages must also b