Journal
NATURE CHEMICAL BIOLOGY
Volume 18, Issue 1, Pages 47-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00899-z
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Funding
- Beijing Natural Science Foundation [JQ20034]
- National Natural Science Foundation of China [21922701, 91853111, 21778005, 31971346, 31861143016]
- National Major Scientific and Technological Special Project for 'Significant New Drugs Development' [2019ZX09739001]
- Shenzhen Institute of Synthetic Biology Scientific Research Program [DWKF20190004]
- National Key R&D Program of China, Synthetic Biology Research [2019YFA0904500]
- Science and Technology Commission of Shanghai Municipality [18JC1411000]
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The engineered NATS system allows for fast therapeutic protein expression triggered by noncanonical amino acids at the translational level, demonstrating potential for next-generation cell-based therapies with orally induced protein expression.
Inducer-triggered therapeutic protein expression from designer cells is a promising strategy for disease treatment. However, as most inducer systems harness transcriptional machineries, protein expression timeframes are unsuitable for many therapeutic applications. Here, we engineered a genetic code expansion-based therapeutic system, termed noncanonical amino acids (ncAAs)-triggered therapeutic switch (NATS), to achieve fast therapeutic protein expression in response to cognate ncAAs at the translational level. The NATS system showed response within 2 hours of triggering, whereas no signal was detected in a transcription-machinery-based system. Moreover, NATS system is compatible with transcriptional switches for multi-regulatory-layer control. Diabetic mice with microencapsulated cell implants harboring the NATS system could alleviate hyperglycemia within 90 min on oral delivery of ncAA. We also prepared ncAA-containing 'cookies' and achieved long-term glycemic control in diabetic mice implanted with NATS cells. Our proof-of-concept study demonstrates the use of NATS system for the design of next-generation cell-based therapies to achieve fast orally induced protein expression.
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