Breaking New Ground in mRNA Degradation

About 85% of disease-related proteins lack suitable binding pockets for conventional drug discovery. While RNA-targeting approaches like siRNAs have shown promise (with several FDA approvals), they struggle with poor cellular uptake, limited tissue specificity, and complex, costly synthesis.

Researchers from Peking University Shenzhen Graduate School introduce a novel modality for targeting “undruggable” proteins through RNA degradation.

New approach- LipoSM-RiboTAC
Liposome-based modality that combines:
→ Self-assembling nanoparticles (~150-160 nm)
→ RNase L-recruiting + RNA-targeting small molecule moieties

After self-assembly, RNase L-recruiting + RNA-targeting small molecule moieties are presented on the surface of the liposome (see figure below).

This represents elaboration of their previous split-and-mix PROTAC platform (link below).

Degradation performance
Three clinically relevant and hard-to-drug targets:
→ MYC DC50: 2.99 μM (western blotting)
→ JUN DC50: 2.93 μM (western blotting)
→ pre-miRNA-155 DC50: 1.44 μM (by RT-qPCR)
All showed concentration- and time-dependent degradation.

My highlights
✓ High specificity – no off-target RNA degradation observed
✓ RNase L-dependent mechanism confirmed through knockdown studies
✓ Significant tumor growth inhibition in mouse models
✓ No apparent toxicity in major organs
✓ Programmable ligand ratios (within the liposome) for optimization
✓ Enhanced cellular delivery
✓ Potential for multitarget applications.
✓ Simplified synthesis and modular design could accelerate drug discovery and enable faster screening of RNA-targeting compounds.

If you saw my recent posts, perhaps you noticed that self-assambling nanoparticles are gaining on popularity.

It would be interesting to see direct comparison of PROTAC and LipoSM-RiboTAC targetting the same protein (or respective RNA).

Share your opinion
What’s your take on RNA-targeted degradation. Is it the next frontier after PROTACs?

Leave your comment under my LinkedIn post here.

The original scientific manuscript has been ublished in JACS:
“Targeted RNA Degradation via LipoSM-RiboTAC Nanoparticles: A Versatile Platform for Cancer Therapy”
https://lnkd.in/e2rve4EU

Paper about split-and-mix PROTAC platform from the same research group:
https://lnkd.in/ep4-7wbr

#DrugDiscovery #InducedProximity #RNATherapeutics