Wang Jiancheng's team published a review article in the Journal of Controlled Release: Non-viral vectors for RNA delivery

Recently, Wang Jiancheng's team from the State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmacy, Peking University published a review article in the Journal of Controlled Release , No.
342 , 2022 .
With the successful launch of RNA drugs, especially the 2019-nCoV vaccine that uses lipid nanoparticles (LNPs) to deliver mRNA , the development of RNA drugs has received more and more attention .

Due to the good advantages of RNA drugs in filling the drug gap of small molecule drug targets, precise treatment and high efficiency, RNA drugs are expected to bring dawn to the treatment of more diseases ^[1-2] .
However, unlike many small molecule drugs and protein drugs, RNA molecules are negatively charged and sensitive to nucleases that are ubiquitous in the body, and their sites of action are mostly located in the cytoplasm ^[3] .
Therefore, overcoming the many obstacles in the RNA delivery process has become the main difficulty restricting the application and transformation of RNA drugs, and it is necessary to design and develop efficient and safe delivery vehicles (Figure 1 ) .

Figure 1.
Non-viral vectors as "delivery trucks" can efficiently and safely deliver RNA drugs in vivo

Therefore, in this review, the team mainly focuses on the research progress of non-viral vectors for RNA delivery in preclinical research, clinical trials and market stage

Figure 2 Extracellular and intracellular barriers for RNA delivery in vivo using non-viral vectors

Summary of highlights from the study:

Classification of non-viral vector designs according to biological barriers to RNA drug delivery in and out of cells

·Overview of non-viral vector research progress of RNA drugs from preclinical, clinical trials and market stages

Synthetic and biomimetic non-viral vectors for RNA drug delivery are discussed separately

In this review, the researchers systematically reviewed the progress of marketed RNA drugs, clinical trials and preclinical research carriers, which effectively protect RNA from ribonuclease degradation, prolong blood circulation in the body, and promote RNA drugs in specific Accumulation in tissues, enhancing cellular internalization of RNA drugs, avoiding intracellular lysosomal degradation, and enhancing intracellular release were comprehensively analyzed

At present, there are 9 kinds of ASO , 4 kinds of siRNA , 2 kinds of mRNA and 1 kind of aptamer drugs on the market, the non-viral vector delivery strategies involved mainly include lipid nanoparticles ( LNP ) and N -acetylgalactosamine ( GalNAc ) covalent coupling
.
Among them are three LNP -based RNA drugs, including Patisiran (ONPATTRO®) , BNT162b2 and mRNA-1273 (see Table 1 ); three GalNAc -conjugated siRNA drugs, including Givosiran , Lumasiran and Inclisiran , are currently in the treatment of liver-related diseases There are significant advantages in the aspect of the system, and there are many drugs in this system in the clinical trial stage (as shown in Table 2 )
.

Table 1.
Carrier formulation components of listed RNA drugs

Table 2 RNA drugs with GalNac coupling technology in the market and in clinical trials

To further promote the clinical translation of more RNA drugs, the safety and efficacy of RNA delivery systems need to be balanced .

The advantages of biomimetic carriers provide new insights into the delivery mode of RNA drugs in vivo, making biomimetic delivery vehicles a future development trend
.
Compared with the complexity of integrating multifunctional modules to synthesize non-viral vectors, biomimetic vectors can obtain complex functional characteristics by introducing a single endogenous module, have good circulation and biocompatibility, and are easily obtained by innate or acquired modification.
Different targeting properties
.
However, there is currently no biomimetic carrier-based RNA drug approved on the market.
The reasons why biomimetic carriers have not yet achieved clinical translation mainly include: potential immunogenicity risks of xenogeneic biological components, potential side effects introduced by complex material compositions, batch-to-batch There are large differences and high difficulty in large-scale production ^[6]
.
The resolution of these issues and the further expansion of available biomaterial sources will drive the development of biomimetic carriers and RNA drug delivery, enabling valuable RNA drugs to truly benefit clinical patients
.

【Article information】

Yi Yan ^# , Xiao-Yu Liu ^# , An Lu, Xiang-Yu Wang, Lin-Xia Jiang, Jian-Cheng Wang*.

Full text link : https://doi.
org/10.
1016/j.
jconrel.
2022.
01.
008

【author information】

Professor Wang Jiancheng from the School of Pharmacy of Peking University is the corresponding author of this article, Yan Yi, a 18th-level doctoral student, and Liu Xiaoyu, a 19th-level direct doctoral student are the co-first authors of this article

Wang Jiancheng, professor and doctoral supervisor of School of Pharmacy, Peking University, member of the Party Committee of School of Pharmacy, vice president of Ningbo Institute of Marine Medicine, Peking University, PI of the State Key Laboratory of Natural Medicines and Biomimetic Drugs, Leading Talent of Science and Technology Innovation of the Ministry of Science and Technology, New Century of the Ministry of Education Outstanding Talent, Beijing Science and Technology Rising Star, Member of the Pharmacy Professional Committee of the Chinese Pharmaceutical Association, Deputy Director of the Pharmacy Professional Committee of the Beijing Pharmaceutical Association, Deputy Editor-in-Chief of the "Chinese Medical Encyclopedia Pharmacy Credit Volume", Member of the National Health and Health Commission 3D Printing Medical Application Expert Committee , Member of Nano Biotechnology Branch of China Pharmaceutical Biotechnology Association, member of Continuing Education Working Committee of China Pharmaceutical Association

【References】

[1] XM Anguela, KA High, Entering the Modern Era of Gene Therapy, Annu Rev Med 70 (2019) 273-288.

[2] MH Miname, VZ Rocha, RD Santos, The Role of RNA-Targeted Therapeutics to Reduce ASCVD Risk: What Have We Learned Recently?, Curr Atheroscler Rep 23(8) (2021).

[3] J.

[4] S.

[5] AS Abu Lila, H.
Kiwada, T.
Ishida, The accelerated blood clearance (ABC) phenomenon: clinical challenges and approaches to manage, J Control Release 172(1) (2013) 38-47.

[6] DD Taylor, S.
Shah, Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes, Methods 87 (2015) 3-10.

(School of Pharmacy, Peking University)