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Updated: Aug 27, 2025
In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction
Published on: January 22, 2020
In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis
Xinyan Zhou1, Mengchao Yu2, Luzhen Ma1
1Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China.
Abstract:
Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.
Insights
This study introduces a novel synthetic biology approach for ulcerative colitis (UC) treatment. It reprograms liver cells to produce extracellular vesicles carrying multiple siRNAs, effectively reducing intestinal inflammation via combination therapy.
Area of Science:
- Synthetic Biology
- Molecular Medicine
- Immunology
Background:
- Ulcerative colitis (UC) is complex, often necessitating combination therapies targeting multiple pathways.
- Current UC treatments using single agents or antibodies have limitations, hindering the full potential of combination therapy.
- Developing novel strategies for effective in vivo delivery of combination therapies is crucial for UC management.
Purpose of the Study:
- To develop a synthetic biology strategy for in vivo combination therapy of ulcerative colitis.
- To engineer liver cells to produce extracellular vesicles loaded with multiple siRNAs for targeted delivery.
- To evaluate the therapeutic efficacy of a multi-targeted genetic circuit against UC in mouse models.
Main Methods:
- Utilized synthetic biology to create artificial genetic circuits for reprogramming liver cells.
- Integrated small extracellular vesicles (sEVs) for in vivo delivery of self-assembled siRNAs.
- Designed a multi-targeted genetic circuit for simultaneous inhibition of TNF-α, B7-1, and integrin α4.
- Employed adeno-associated virus (AAV) vectors for sustained gene expression and therapeutic effect.
Main Results:
- Engineered liver cells secreted sEVs containing multiple siRNAs, enabling combination therapy for UC.
- Repeated injections of the multi-targeted circuit rapidly reduced intestinal inflammation and exerted synergistic effects.
- The therapy suppressed pro-inflammatory cascades, T cell costimulatory signals, and T cell homing to inflamed areas.
- A single injection of the AAV-driven circuit achieved substantial and lasting inhibition of target molecules.
Conclusions:
- Established a feasible combination therapeutic strategy for ulcerative colitis using synthetic biology and extracellular vesicles.
- Demonstrated the potential of this approach as an alternative to conventional biological therapies requiring multiple agents.
- Highlighted the therapeutic benefits of simultaneously targeting TNF-α, B7-1, and integrin α4 for UC treatment.
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