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Figure 1. 

Development history of targeted degradation and modulation technologies: from proteins to RNAs. PROTACs induce intracellular protein degradation by recruiting target proteins to E3 ubiquitin ligases, thereby triggering ubiquitination and subsequent proteasomal degradation. Molecular glues promote the interaction between target proteins and E3 ligases, leading to degradation mediated by the ubiquitin–proteasome system. LYTACs internalize extracellular or membrane-associated proteins and deliver them to lysosomes for degradation. Autophagy-targeting chimeras, represented by AUTOTACs, mediate target protein degradation through the autophagy–lysosome pathway. Phosphorylation-targeting chimeras (PhosTACs) achieve targeted protein dephosphorylation by recruiting phosphatases. In parallel, RNA-targeting strategies have progressed from RNA-binding small molecules that modulate RNA function without inducing RNA degradation to RNA-cleaving conjugates capable of directly cleaving target RNAs, and further to RiboTACs, which recruit endogenous RNase L to achieve catalytic RNA degradation.

Figure 2. 

Representative interaction patterns between small molecules and various target RNAs. (a) Small molecules bind to the Drosha or Dicer cleavage sites of miRNA precursors to block its maturation process. (b) Small molecules interact with the IRES of certain pathogenic mRNAs, inhibiting the translation process. (c) Small molecules attach to the repeat regions of certain mRNAs, causing nervous system-related diseases. (d) Small molecules influence the spatial structure of certain mRNA precursors to affect splicing and inhibit the expression of pathogenic proteins.

Figure 3. 

Small molecule-RNA binding patterns and interaction modes. (a) Three classes of small molecules interacting with pri-miR-96. (b) Binding methods, affinity, and inhibitory effects of different compounds toward pri-miR-96. The orange sequences in (b) present mature miRNA-96.

Figure 4. 

Structures of RNA-bound benzimidazoles.

Figure 5. 

Structures of aminoglycosides, polyamines, and other compounds.

Figure 6. 

Structures of currently reported RiboTAC molecules. The green moieties represent RNase L-recruiting groups, whereas the blue moieties represent RNA-binding groups.

Figure 7. 

Optimization of RiboTACs. (a) Classification and screening strategies for the RNA binding part. (b) The linker of RiboTACs is generally a combination of PEG and peptides. (c) Reported RNase L activators. (d) Tags used in RiboTACs. (e) FRET-based RNA model for the RNase L activators screen. When RNase L is dimerized and activated by 2'-5'A or other small molecules, it cleaves the RNA and displays fluorophores.