Human proteins transform into mRNA "delivery trucks" Tsinghua University develops new vector for cancer immunotherapy

[Reporter Hong Meixiu/Hsinchu Report] A research team from Tsinghua University used the body's original PEG10 protein to develop a new protein nanoparticle (PBNP) that can self-package mRNA. It also improved the manufacturing process through genetic engineering to increase the efficiency of mRNA entering cancer cells. Research by the team of Hu Yucheng, Tsinghua Chair Professor of the Department of Chemical Engineering, found that PBNP loaded with immunotherapy mRNA and used in combination with chemotherapy drugs can inhibit tumor growth and enhance immune response in colorectal cancer animal experiments. This research was also published in the international journal "Nature Communications".

Tsinghua University pointed out that mRNA is the instruction for cells to make proteins, but it is easy to break down and difficult to enter cells on its own. It needs carriers to assist in transporting it. Currently commonly used lipid nanoparticles (LNP) usually require the production of mRNA first and then encapsulation through multiple procedures. Hu Yucheng's team instead used baculovirus (BV) to deliver the required genes into production cells. After the cells produce the PEG10 protein and the designed mRNA, the PEG10 protein assembles itself into nanoparticles and packages the mRNA within them. Compared with traditional methods, the new process reduces manufacturing costs, and the ability to effectively deliver mRNA per milliliter of PBNP preparation is also increased by 11.3 times. The prepared PBNP can still maintain the integrity and delivery function of mRNA after being refrigerated at 4 degrees Celsius for 7 months.

The Tsinghua team transformed the original proteins of the human body into the mRNA "delivery truck" PBNP, allowing cells to complete packaging first, and then deliver the mRNA to cancer cells, becoming a new vehicle for the development of cancer immunotherapy.

Hu Yucheng likened PBNP to a "delivery truck" and mRNA is the cargo carried on the truck. Through genetic engineering to modify the surface of the particles, antibody fragments that can recognize epidermal growth factor receptor (EGFR) were added. After many ratio adjustments, PBNP was finally able to combine the ability to recognize and enter cancer cells.

After confirming that PBNP could deliver mRNA into cells, the team further switched to mRNA that allowed the cells to produce two immune regulatory proteins, IL-12 and OX40L. Experiments have found that cancer cells can produce these two proteins according to instructions. When co-cultured with immune cells, an increase in T cell activation was also observed. In animal models, researchers injected PBNP into tumors and treated them with the chemotherapy drug oxaliplatin. Compared with either therapy alone, combined therapy can inhibit tumor growth and enhance immune response, and preliminary observations have shown no obvious acute toxicity.