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  3. Engineered platelets as targeted protein degraders and application to breast cancer models

Engineered platelets as targeted protein degraders and application to breast cancer models

  • Nat Biotechnol. 2024 Dec 3. doi: 10.1038/s41587-024-02494-8.
Yu Chen 1 2 3,  Samira Pal 1,  Wen Li 1,  Fengyuan Liu 1,  Sichen Yuan 1 2 3,  Quanyin Hu 4 5 6
Affiliations

Affiliations

  • 1 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
  • 2 Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
  • 3 Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
  • 4 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. qhu66@wisc.edu.
  • 5 Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. qhu66@wisc.edu.
  • 6 Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. qhu66@wisc.edu.
PMID: 39627511 DOI: 10.1038/s41587-024-02494-8
Abstract

Clinical application of chimeric molecules for targeted protein degradation has been limited by unfavorable drug-like properties and biosafety concerns arising from nonspecific biodistribution after systemic administration. Here we develop a method to engineer platelets for degradation of either intracellular or extracellular proteins of interest (POIs) in vivo by covalently labeling heat shock protein 90 (HSP90) in platelets with a POI ligand. The degrader platelets (DePLTs) target wound areas and undergo activation. Depending on the tethered POI ligand and transport mechanism of the prelabeled HSP90, activated DePLTs can mediate targeted protein degradation in the target cell through the ubiquitin-proteasome machinery or the lysosome. HSP90 packaged into platelet-derived microparticles uses the ubiquitin-proteasome system to degrade intracellular POIs, whereas released free HSP90 redirects extracellular POIs to lysosomal degradation. In postsurgical breast Cancer mouse models, DePLTs engineered with corresponding POI ligands effectively degrade intracellular bromodomain-containing protein 4 or extracellular programmed cell death ligand 1, thereby suppressing Cancer recurrence or metastasis.

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