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Trans-splicing denoiser circuits enable highly sensitive cellular sensors for physiological biomarkers
Sheng-Yan Chen1, Yuanli Gao1, Yi Fan2
1College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China.
Biosensors & Bioelectronics
|June 25, 2025
Summary
We developed a novel pipeline to optimize whole-cell biosensors for detecting uric acid and lactate. This system enables portable, on-site biomarker detection for metabolic disorder diagnostics.
Area of Science:
- Synthetic biology
- Biomedical engineering
- Analytical chemistry
Background:
- Whole-cell biosensors have limitations in detecting physiological biomarkers, including narrow dynamic ranges and low sensitivity.
- Existing methods often require specialized equipment, hindering on-site diagnostics.
Purpose of the Study:
- To establish a generalizable synthetic biosensor optimization pipeline.
- To develop portable, paper-based colorimetric sensing devices for on-site detection of uric acid and lactate.
- To improve the dynamic range and sensitivity of whole-cell biosensors.
Main Methods:
- Developed a universal split intron-mediated trans-splicing denoiser to reduce leakage expression and enhance dynamic range.
- Integrated trans-splicing denoisers with transcriptional optimization strategies (promoter engineering, receptor/transporter density tuning).
- Engineered fluorescent biosensors for uric acid and lactate detection.
- Devised a paper-based colorimetric sensing chip with a portable detection platform and analysis software.
Main Results:
- Reduced leakage expression by over 21-fold and boosted dynamic ranges by 9-fold using trans-splicing denoisers.
- Achieved excellent limits of detection (0.8 μM for uric acid, 0.5 mM for lactate) and wide dynamic ranges (up to 1500-fold) for fluorescent biosensors.
- Demonstrated visualization of quantified uric acid (1-8 μM) and lactate (0.25-16 mM) in artificial urine using the paper-based colorimetric sensing chip.
- The integrated system provides portable, cost-effective on-site biomarker visualization.
Conclusions:
- The developed pipeline offers a systematic and adaptable approach for optimizing whole-cell biosensors.
- The portable paper-based sensing system enables rapid, on-site detection of critical metabolic biomarkers.
- This technology accelerates the application of whole-cell biosensors in healthcare diagnostics and metabolic disorder monitoring.
