Recently, Huang Yuanyu’s research group of BIT has made new progress in the combination of small interfering ribonucleic acid (siRNA) and photodynamic therapy (PDT) in the treatment of liver cancer. The related research paper is published on ACS Applied Materials & Interfaces, a top journal, entitled ROS-Activatable siRNA-Engineered Polyplex for NIR-Triggered Synergistic Cancer Treatment (IF= 8.758). Zhang Mengjie, doctoral student of BIT, is the first author of this paper, whose corresponding author is Researcher Huang Yuanyu.

As the main type of RNA interference (RNAi), siRNA is one of the emerging representative technologies in the field of biopharmaceuticals in the future. At present, 3 siRNA drugs (Onpattro, Givlaari, Oxlumo) have been approved for marketing worldwide. However, effects could only be taken if the siRNA drugs have been in the cytoplasm. Therefore, how to efficiently enter the cell and further efficiently escape from the endosome to the cytoplasm is a very important and challenging scientific problem. Photodynamic therapy (PDT) is a new method of using photosensitive drugs and lasers to treat specific diseases. In the presence of oxygen, irradiating the diseased area with a specific wavelength can selectively activate the photosensitive drugs in the diseased tissue. The reactive oxygen species (ROS) generated in this process can kill the target tissue and cells to realize the treatment. At the same time, some studies have shown that ROS can improve the permeability of cell membrane and endosome membrane, which will be conducive to the entry of siRNA drugs into the cell and the escape of endosomes.

Fig. 1 Mechanism and research ideas of PPTC / siRNA

Based on the above considerations, the research designed a polyethylene glycol (PEG) modified, ROS-responsive cationic polymer PPTC, which can efficiently load anti-RRM2 gene siRNA drugs to form a stable and uniform PPTC/siRRM2 nanodrug system. RRM2 is a deoxyribonuclease reducing subunit, which is closely related to the occurrence and development of various cancers. Silencing RRM2 can promote tumor cell apoptosis. After entering the cell, under the irradiation of near-infrared light, it can effectively degrade the polymer and generate ROS that can destroy the endosome membrane and promote the escape of endosome, and destroy the cell membrane to cause tumor cells apoptosis. The siRNA that enters the cytoplasm inhibits the expression of RRM2, which can effectively prevent the proliferation of cancer cells, thereby achieving synergistic anti-tumor therapy from the perspective of “promoting apoptosis and inhibiting proliferation” (Fig. 1).

Fig. 2 Study on the effect and mechanism of PPTC/siRNA compound at the cellular level

The researchers first transfected the siRNA drug system into hepatoma cells, and the results of confocal laser microscopy showed that the system could enter into the cells efficiently; moreover, compared with the non-light group, the escape efficiency of siRNA endosomes was effectively improved after light treatment (Fig. 2A). The study of BioTEM has proved that the ROS generated by the system after light exposure can effectively improve the permeability of cell membranes and kill tumor cells (Fig. 2B).

Fig. 3 Study on the efficacy of PPTC/siRNA in CDX and PDX tumor models

Furthermore, the CDX model of xenotransplantation of hepatoma cell lines in mice (Fig. 3A-C) and the PDX tumor model of xenotransplantation of cancer tissue from patients with hepatocellular carcinoma (Fig. 3D-F) are established, and the results show that PPTC / siRNA drug system can effectively inhibit tumor growth and promote cancer cell apoptosis. It is worth noting that the data proves that the drug system shows a good synergistic effect of photodynamic and siRNA therapy. Compared with siRNA alone or light treatment alone, the combination of the two can significantly increase the gene silencing efficiency of RRM2 and enhance the inhibition effect of tumor growth in mice (Figure 3A-B). Besides, the compound shows good safety in both cells and animals.

This paper provides new ideas on how to improve the delivery efficiency of siRNA drugs (entering target cells, escaping endosomes and reaching the cytoplasm), and provides an example for siRNA drugs triggered by near-infrared light and photodynamic anti-tumor therapy.

About the author:

Researcher Huang Yuanyu, the leader of his research group and a PhD supervisor of BIT, has published over 50 SCI papers on Nano Today, Adv Funct Mater, Nano Lett, and Biotechnol Adv, etc., in which, he is the first author or the corresponding author of over 30 papers, including 13 paper with IF>10 and 3 highly cited papers of ESI. Besides, he has written 6 monographs, 1 Chinese textbook; 6 patent applications, including 2 authorized PCT patents. Researcher Huang has also successively presided over more than 10 projects with National Natural Science Foundation of China included, and was selected as Beijing Science & Technology star (2020) and advanced worker of Beijing Association for Science and Technology (2020). Moreover, he is the Secretary General and the Director of Nanobiology Branch of Biophysical Society of China, Director or Member of other four societies, as well as the editorial board member of several journals.

Paper details: Mengjie Zhang, Yuhua Weng, Ziyang Cao, Shuai Guo, Bo Hu, Mei Lu, Weisheng Guo, Tongren Yang, Chunhui Li, Xianzhu Yang, and Yuanyu Huang*. ROS-Activatable siRNA-Engineered Polyplex for NIR-Triggered Synergistic Cancer Treatment. ACS Appl. Mater. Interfaces 2020, 12, 32289−32300.

Teacher Homepage: http://arims.bit.edu.cn/xzdw/qnggjs/tbyjy/178349.htm

Paper link: https://dx.doi.org/10.1021/acsami.0c06614