Beyond the Cell: The New Frontier of Extracellular Protein Degradation
- Extracellular Targeted Protein Degraders (eTPDs) like LYTACs are a new technology designed to eliminate disease-causing proteins located outside of the cell.
- These molecules work by linking an external target protein to a cell-surface receptor, triggering internalization and degradation in the lysosome.
- This approach significantly expands the range of “degradable” targets, opening new therapeutic avenues for oncology, immunology, and other fields.
- Targeted degradation of extracellular proteins: state of the art and future directions:
https://pubmed.ncbi.nlm.nih.gov/40307925/ - 10 Evolved Terms Every Scientist Should Know About Targeted Protein Degradation in 2025:
https://resources.nanotempertech.com/blog/10-evolved-terms-every-scientist-should-know-about-targeted-protein-degradation-in-2025 - Targeted protein degradation: advances in drug discovery and therapeutic applications:
https://www.nature.com/articles/s41392-024-02004-x
The development of Targeted Protein Degraders (TPDs) like PROTACs marked a paradigm shift in medicine. By co-opting the cell’s internal machinery to destroy disease-causing proteins, we moved from simply inhibiting targets to eliminating them entirely. However, this revolution was confined within the cell walls. The vast landscape of extracellular proteins—secreted signaling molecules and cell-surface receptors that drive diseases like cancer and autoimmune disorders—remained beyond the reach of this powerful technology, as the cell’s disposal systems operate internally.
A new class of molecules is now taking protein degradation beyond the cell’s borders. Extracellular TPDs (eTPDs), including technologies like LYTACs (Lysosome-Targeting Chimeras), are designed to tackle these external threats. A LYTAC molecule acts as a molecular bridge: one end binds to a disease-causing protein floating outside the cell, while the other latches onto a receptor on the cell’s surface. This connection triggers the cell to internalize the entire complex through endocytosis, delivering the target protein to the lysosome—the cell’s “incinerator”—for complete destruction.
This innovative approach dramatically expands the “degradable” proteome, opening up a wealth of previously untreatable targets. Scientists are no longer limited to the proteins inside a cell, but can now design degraders for secreted growth factors that fuel tumors or cell-surface receptors that mediate inflammation. This technology is still in its early days, but it represents a crucial evolution in the TPD field. By extending our reach to the extracellular space, we are unlocking powerful new strategies to fight disease at its source, wherever that may be.