Escape From the Endosome!

Nanotube Bundles
Nanotube bundles (yellow) containing RNA enter a cell. From left to right, the images show the endosomes (red) surrounding the nucleus (blue) of the cell begin to swell. Around the 3 hour mark, the endosomes burst and spill the RNA payload (green). The RNAs spread throughout the cell over the next two days (Contributed photo).

Most drugs are small. But large molecules could be enormously useful medicines—if we could only get them inside our cells. Now, a group of researchers in biomedical engineering – a shared department with the UConn School of Dental Medicine, School of Medicine, and School of Engineering – has developed a non-toxic way to do just that.

Pfizer and Moderna’s COVID-19 vaccines have demonstrated just how useful large biomolecule drugs can be. Their vaccines are based on messenger ribonucleic acid (mRNA) which is a molecule hundreds of times bigger than a typical small-molecule drug.

Small molecules have it easy. They can slip into our cells undetected and do their work without fear of getting captured and digested by endosomes. Endosomes are like tiny bubble stomachs that envelope large molecules seeking entry to cells and digest them with acid.

UConn associate professor of biomedical engineering Yupeng Chen, his student Jinhyung Lee, and other members of his lab describe in the May 11 issue of PNAS a way to protect large biomolecule drugs by encasing them in a nanomaterial mimicking DNA. Nanomaterials are objects designed at the atomic scale; they’re usually only slightly larger than large molecules. The material Chen’s lab used is shaped like a bundle of sticks, where the sticks are tubes of DNA-like nanotubes. The DNA nanotube acts like a sponge for acid, sucking up the free hydrogen atoms in the acid that would otherwise do the damage, and tricking the endosome into pumping more and more water and acid inside of itself until it explodes.

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