Abstract
The vast majority of the human genome codes for RNA, but RNA-targeting therapeutics account for a small fraction of approved drugs. As such, there is great incentive to improve old and develop new approaches to RNA targeting. For many RNA targeting modalities, just binding is not sufficient to exert a therapeutic effect; thus, targeted RNA degradation and induced decay emerged as powerful approaches with a pronounced biological effect. This review covers the origins and advanced use cases of targeted RNA degrader technologies grouped by the nature of the targeting modality as well as by the mode of degradation. It covers both well-established methods and clinically successful platforms such as RNA interference, as well as emerging approaches such as recruitment of RNA quality control machinery, CRISPR, and direct targeted RNA degradation. We also share our thoughts on the biggest hurdles in this field, as well as possible ways to overcome them.