Yang Zhenjun's team made new progress in the study of in vivo delivery of cyclic diguanylate and its analogues and the mechanism of tumor immune action

Nucleic acids are an important class of biological molecules capable of storing genetic information, and their own and encoded functional proteins are involved in many life processes
.
A variety of functional oligonucleotides used to regulate gene-level physiological processes and disease treatment are current research hotspots, including antisense nucleic acids (ASOs), small interference RNAs (siRNA), miRNAs (microRNAs), ribozymes, nucleic acid aptamers, mRNAs, plasmids, and cyclic dinucleotides (cDNs
).
Its physiological conditions are negatively charged, and overcoming environmental barriers in the body and effectively delivering them is an urgent problem
that needs to be solved.

Professor Yang Zhenjun, a team of Professor Yang Zhenjun of the State Key Laboratory of Natural and Biomimetic Drugs of Peking University School of Pharmacy, developed a nanopreparation of neutral cytidine lipids (DNCA) combined with cystine skeleton cationic lipids CLD, which combines hydrogen bonding/π-π accumulation and electrical effects with nucleic acid drugs, and has realized the paratumor injection administration of nucleic acid aptamers (Biomaterials, 2018), antisense nucleic acids (Biomaterials, 2019), siRNA (Mol Ther) and so on Nucleic Acids, 2021) Intravenous administration and intramuscular administration of the new crown mRNA vaccine (J Control Release, 2021), the treatment effect was remarkable, the hepatorenal toxicity was very low, and no immunogenicity was observed
.

In the study of the druggability of cyclic diguanylate and its analogues, Professor Yang Zhenjun's team realized the efficient cell transfection and in vivo delivery of such drugs based on the hybrid lipid DNCA/CLD (Mix) delivery system, and the optimized cdG/Mix induced IFN-I.
ability was 50 times that of uncoated cdG, which could induce immunogenic death (0.
5~1.
4 μM)
of melanoma and breast cancer cells 。 Both intra-cdG/Mix tumor (0.
1 mg/only) and intravenous (2 mg/only) can significantly inhibit the tumor growth of breast cancer and melanoma mice, realize the systemic activation and recruitment of CD8⁺ T and NK cells in tumor-bearing mice, ~43% of mice achieve long-term survival, and 83% of long-term surviving mice are re-inoculated with tumors without tumor growth, resulting in tumor-specific immune memory
。 The study reported for the first time a novel mechanism of cdG/Mix tumor immunotherapy effect, namely reversing the T cell depletion (Tex) state throughout the tumor-bearing mouse, and significantly reducing the mRNA expression levels of the key factors for Tex development in CD8⁺ T cells
, Tox and Nr4a.

The result, "Novel formulation of c-di-GMP with cytidinyl/cationic lipid reverses T cell exhaustion and activates stronger anti-tumor immunity" was published in the journal Theranostics in September 2022 (doi:10.
7150/ thno.
71010)
。 Yu Xiaotong (2018 Ph.
D.
student of School of Pharmacy) and Ph.
D.
student of School of Pharmacy of Peking University (2016 undergraduate student of School of Pharmacy) are co-first authors of the paper, and Professor Yang Zhenjun of the State Key Laboratory of Natural and Bionic Drugs of Peking University is the corresponding author
of the paper.

The above research is supported by the major special project of new drugs of the Ministry of Science and Technology of China (2017ZX09303013), the key project of the National Natural Science Foundation of China and the Henan Provincial Joint Fund (No.
2017ZX09303013) and the National Natural Science Foundation of China (21572013
).

About Professor Yang Zhenjun

Zhenjun Yang is a professor at the School of Pharmacy, Peking University Medical College, and PI,
State Key Laboratory of Natural and Biomimetic Drugs.
He received his bachelor's degree in pharmacy from Beijing Medical University in 1987, his Ph.
D.
in medicinal chemistry from Beijing Medical University in 1998, and his postdoctoral research at the School of Pharmacy of the University of Georgia from 2000 to 2002
.
He once served as the deputy director of the Department of Medicinal Chemistry, the director of the Chemical Biology Flow Project of the Department of Chemistry of the National Natural Science Foundation of China, and is currently a member of the Chemical Biology of the Chinese Chemical Society and the Medicinal Chemistry Professional Committee of the
Chinese Pharmaceutical Society.
Main research directions:1.
Chemical modification of nucleic acid drugs and research on novel targeted preparations; 2.
Research on new technologies for early detection of diseases based on nucleic acid aptamers; 3.
Molecular chemical biology of cyclic nucleotide messengers; 4.
Nucleoside antiviral drug research
.
He has published more than 160 research papers and applied for and authorized 26 patents
.
He is responsible for the major special projects of new drugs of the Ministry of Science and Technology, the 973 project projects, the major 863 project projects, the key projects of the Natural Science Foundation of China and a number of
topics.
He has won 1 first prize and 2 second prizes of natural science of the Ministry of Education, and 1 second prize of national natural science
.

(State Key Laboratory of Natural and Biomimetic Drugs, College of Pharmacy)