Reprogramming CAR T-Cells with designed bioPROTACs
Gene editing has been used to enhance CAR T-cell function by disrupting negative regulators but has limitations. Here we show that de novo-designed generated targeted degraders (bioPROTACs) provide an alternative approach. Expression of bioPROTACs in CAR T-cells targeting DNMT3A, a key regulator of T-cell exhaustion, phenocopied gene knockout. Our reversible, non-gene editing approach provides a tunable strategy to reprogram T-cell fate which should be broadly applicable for next-generation cell therapies.
Authors
- Tian Mi
- Tae Gun Kang (ORCID: https://orcid.org/0000-0002-2997-9887)
- Francesca Ferrara (ORCID: https://orcid.org/0000-0002-4973-1520)
- Anthony A. High (ORCID: https://orcid.org/0000-0003-2323-5649)
- Yu Kaiwen
- Adeleye O. Adeshakin (ORCID: https://orcid.org/0000-0002-2818-2059)
- Sebastian Kenny (ORCID: https://orcid.org/0000-0003-3541-2577)
- Dionne Vafeados (ORCID: https://orcid.org/0000-0002-2560-8907)
- Robert E. Throm (ORCID: https://orcid.org/0000-0002-9191-4742)
- Ben Youngblood (ORCID: https://orcid.org/0000-0002-1261-9957)
- Rahul S. Kathayat (ORCID: https://orcid.org/0000-0002-9159-2413)
- Vivek S. Peche (ORCID: https://orcid.org/0000-0003-3415-8765)
- David L. Baker (ORCID: https://orcid.org/0000-0002-0664-6780)
- Andrew Nemecek
- Martin Reid
- Brian Coventry
- Inna Goreshnik
- Zuo-Fei Yuan
- Macey Smith
- Stephen Gottschalk
- Long Wu
- Elizabeth Wickmann
- Taosheng Chen
Institutions
- St. Jude Children's Research Hospital (US)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Vector (United States) (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-22
- DOI
- https://doi.org/10.64898/2026.02.21.706835
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00