There are three key points in RNA drug R&D.

First, the immunogenicity of RNA drugs: Because foreign RNA will be recognized by the immune system as a signal of virus interference, RNA drugs will more or less stimulate the immune system and cause a series of side effects.

Second, the stability of RNA drugs: There are a large number of ribonucleases (RNases) in human blood and tissue fluid, and naked RNAs that have not been chemically modified are usually destroyed before entering the cell. In addition, the efficiency of mRNA translation is also closely related to its stability in the cell.

Third, the delivery of RNA drugs: RNA molecules are charged and cannot freely traverse the cell membrane structure. Therefore, transmembrane transport and endosome escape are problems that cannot be avoided in the design of RNA drugs. In addition, how to achieve targeted delivery is also the focus of current research.

Delivery system (https://mrna.creative-biolabs.com/custom-delivery-vehicle-for-mrna.htm)
An excellent delivery system must have the following characteristics.
1. Able to bind RNA molecules to form complexes.
2. Can promote the uptake of cells.
3. Can protect RNA molecules from degradation by nucleases outside the cell.
4. Able to release RNA molecules into the cytoplasm.
5. The delivery vehicle itself must not be toxic.

In addition to the above-mentioned basic requirements, achieving the targeted delivery of RNA molecules is the current target of the next generation of vectors. The systems that are being developed or put into commercial use are mainly divided into three categories, nanoparticle delivery systems, covalently coupled modified delivery systems, and exosome delivery systems. The most common viral vector delivery system in the field of gene therapy is more used for DNA-based therapies.

Modification
The main purpose of RNA modification is to solve some of the problems of natural RNA molecules themselves, including immunogenicity, enzyme stability, target affinity, and mRNA translation efficiency. According to the modified position and structure, chemical modification can be divided into base modification, ribose modification (https://mrna.creative-biolabs.com/nucleotides-modification.htm), and phosphate backbone modification.

In base modification, a more successful strategy is to replace cytidine (C) with 5-methylcytidine (m5C) or replace uridine (U) with pseudouridine (ψ) to make the modified mRNA can escape from the immune system. These two modifications were first invented by biochemists Katalin Karikó and Drew Weissman at the University of Pennsylvania, and they immediately applied for a patent.

Synthesis
The synthesis of RNA is mainly divided into chemical synthesis and biosynthesis. The advantage of chemical synthesis is that it can be produced on bulky scale, but the cost is relatively high, and it is generally only suitable for short-chain RNA such as siRNA and ASO, while molecular length and secondary structure are the main factors that make the synthesis of long-chain mRNA difficult. Therefore, when it is necessary to synthesize long-chain RNA with more than 40 bases, biosynthesis is required.

The reason why 2018 is a turning point for the RNA therapy industry, apart from the two major milestones of Moderna's listing and the approval of patisiran, the most important thing is that the attitude of the capital market changed in nature. As of March 2021, the total amount of post-listing refinancing of NASDAQ RNA-listed companies exceeded 7 billion USD, of which 70% of the post-listing refinancing occurred in 2018 and beyond.

From scientists first confirmed the existence of mRNA in 1961 to the advent of the COVID-19 mRNA vaccine in 2020, scientists have gone through a whole lot of knowledge, development, and utilization of RNA. In recent years, the emergence of multiple ASO drugs, RNAi drugs, and COVID-19 mRNA vaccines has brought more and more capital to pay attention to the development of RNA therapy.

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