Synthetic RNA-based switches provide distinctive merits in modulating gene expression.Simple and flexible RNA-based switches are crucial for advancing the field of gene regulation,paving the way for innovative tools t...Synthetic RNA-based switches provide distinctive merits in modulating gene expression.Simple and flexible RNA-based switches are crucial for advancing the field of gene regulation,paving the way for innovative tools that can sense and manipulate cellular processes.In this research,we have developed programmable ribozymes that are capable of suppressing gene expression in response to specific,endogenously expressed trigger RNAs.We engineer ribozymes by introducing upstream antisense sequences(anti-ribozymes)to inhibit the self-cleaving activity of the hammerhead ribozyme and open the expression of the target gene.The trigger RNA is designed to recognize and bind to complementary sequences within the anti-ribozymes,thereby inhibiting their ability to direct protein synthesis.The anti-ribozyme performance is optimized by regulating the essential sequence modules that play a crucial role in determining the specificity and efficiency of the anti-ribozyme’s interaction with its trigger RNA.By applying this switch mechanism to various ribozyme designs,we have shown that it is possible to achieve control over gene expression across a wide range of trigger RNAs.By exploiting these pro-grammable anti-ribozymes,we aim to create a powerful tool for controlling gene expression in mammalian cells,which could have important implications for basic research,disease diagnosis,and therapeutic interventions.展开更多
The disruption and reconstruction of the TREM2^(+) tissue resident macrophage(TRM)barrier on the surface of synovial lining play a key role in the activation and"remission"of rheumatoid arthritis(RA),which e...The disruption and reconstruction of the TREM2^(+) tissue resident macrophage(TRM)barrier on the surface of synovial lining play a key role in the activation and"remission"of rheumatoid arthritis(RA),which engender the prediction of this immunologic barrier as a potential driver for the achievement of"cure"in RA.However,strategies to promote the reconstruction of this barrier have not been reported,and the effect of patching this barrier remains unidentified.On the other hand,appropriate piezoelectric stimulation can reprogram macrophages,which has never been exerted on this barrier TRM yet.Herein,we design piezoelectric tetragonal BaTiO_(3)(BTO)ultrasound-driven nanorobots(USNRs)by the solvothermal synthesis method,which demonstrates satisfactory electro-mechanical conversion effects,paving the way to generate controllable electrical stimulation under ultrasound to reprogram the barrier TRM by minimally invasive injection into joint cavity.It is demonstrated that the immunologic barrier could be patched by this USNR effectively,thereby eliminating the hyperplasia of vessels and nerves(HVN)and synovitis.Additionally,TREM2 deficiency serum-transfected arthritis(STA)mice models are applied and proved the indispensable role of TREM2 in RA curing mediated by USNR.In all,our work is an interesting and important exploration to expand the classical tetragonal BTO nanoparticles in the treatment of autoimmune diseases,providing a new idea and direction for the biomedical application of piezoelectric ceramics.展开更多
As the most abundant biological entities with incredible diversity,bacteriophages(also known as phages)have been recognized as an important source of molecular machines for the development of genetic-engineering tools...As the most abundant biological entities with incredible diversity,bacteriophages(also known as phages)have been recognized as an important source of molecular machines for the development of genetic-engineering tools.At the same time,phages are crucial for establishing and improving basic theories of molecular biology.Studies on phages provide rich sources of essential elements for synthetic circuit design as well as powerful support for the improvement of directed evolution platforms.Therefore,phages play a vital role in the development of new technologies and central scientific concepts.After the RNA world hypothesis was proposed and developed,novel biological functions of RNA continue to be discovered.RNA and its related elements are widely used in many fields such as metabolic engineering and medical diagnosis,and their versatility led to a major role of RNA in synthetic biology.Further development of RNA-based technologies will advance synthetic biological tools as well as provide verification of the RNA world hypothesis.Most synthetic biology efforts are based on reconstructing existing biological systems,understanding fundamental biological processes,and developing new technologies.RNA-based technologies derived from phages will offer abundant sources for synthetic biological components.Moreover,phages as well as RNA have high impact on biological evolution,which is pivotal for understanding the origin of life,building artificial life-forms,and precisely reprogramming biological systems.This review discusses phage-derived RNA-based technologies terms of phage components,the phage lifecycle,and interactions between phages and bacteria.The significance of RNA-based technology derived from phages for synthetic biology and for understanding the earliest stages of biological evolution will be highlighted.展开更多
基金supported by a grant from the Ministry of Science and Technology of the People’s Republic of China(Grant No.2021YFC2101700 and Grant No.2018YFA0900100)National Key Research and Development Program of China(Grant No.2021YFA0910700)+1 种基金the Chinese Academy of Sciences[No.XDB0480100 of the Strategic Priority Research Program]and CAS Youth Interdisciplinary TeamThis work was also supported by Vanke Special Fund for Public Health and Health Discipline Development,Tsinghua University(2022Z82WKJ006).
文摘Synthetic RNA-based switches provide distinctive merits in modulating gene expression.Simple and flexible RNA-based switches are crucial for advancing the field of gene regulation,paving the way for innovative tools that can sense and manipulate cellular processes.In this research,we have developed programmable ribozymes that are capable of suppressing gene expression in response to specific,endogenously expressed trigger RNAs.We engineer ribozymes by introducing upstream antisense sequences(anti-ribozymes)to inhibit the self-cleaving activity of the hammerhead ribozyme and open the expression of the target gene.The trigger RNA is designed to recognize and bind to complementary sequences within the anti-ribozymes,thereby inhibiting their ability to direct protein synthesis.The anti-ribozyme performance is optimized by regulating the essential sequence modules that play a crucial role in determining the specificity and efficiency of the anti-ribozyme’s interaction with its trigger RNA.By applying this switch mechanism to various ribozyme designs,we have shown that it is possible to achieve control over gene expression across a wide range of trigger RNAs.By exploiting these pro-grammable anti-ribozymes,we aim to create a powerful tool for controlling gene expression in mammalian cells,which could have important implications for basic research,disease diagnosis,and therapeutic interventions.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.52072210 and 52111530230)Key R&D Projects of Social Development of Hainan Provincial Department of Science and Technology(Grant No.ZDYF2020137)Tsinghua University Beijing Union Medical CollegeeHospital Cooperation Project(Grant No.20191080871).
文摘The disruption and reconstruction of the TREM2^(+) tissue resident macrophage(TRM)barrier on the surface of synovial lining play a key role in the activation and"remission"of rheumatoid arthritis(RA),which engender the prediction of this immunologic barrier as a potential driver for the achievement of"cure"in RA.However,strategies to promote the reconstruction of this barrier have not been reported,and the effect of patching this barrier remains unidentified.On the other hand,appropriate piezoelectric stimulation can reprogram macrophages,which has never been exerted on this barrier TRM yet.Herein,we design piezoelectric tetragonal BaTiO_(3)(BTO)ultrasound-driven nanorobots(USNRs)by the solvothermal synthesis method,which demonstrates satisfactory electro-mechanical conversion effects,paving the way to generate controllable electrical stimulation under ultrasound to reprogram the barrier TRM by minimally invasive injection into joint cavity.It is demonstrated that the immunologic barrier could be patched by this USNR effectively,thereby eliminating the hyperplasia of vessels and nerves(HVN)and synovitis.Additionally,TREM2 deficiency serum-transfected arthritis(STA)mice models are applied and proved the indispensable role of TREM2 in RA curing mediated by USNR.In all,our work is an interesting and important exploration to expand the classical tetragonal BTO nanoparticles in the treatment of autoimmune diseases,providing a new idea and direction for the biomedical application of piezoelectric ceramics.
基金This work was financially supported by National Key Research and Development Project of China(Grant No.2018YFA0900103)International Cooperation and Exchange of the National Natural Science Foundation of China(Grant No.31961133019)National Natural Science Foundation of China(Grant No.31670991).
文摘As the most abundant biological entities with incredible diversity,bacteriophages(also known as phages)have been recognized as an important source of molecular machines for the development of genetic-engineering tools.At the same time,phages are crucial for establishing and improving basic theories of molecular biology.Studies on phages provide rich sources of essential elements for synthetic circuit design as well as powerful support for the improvement of directed evolution platforms.Therefore,phages play a vital role in the development of new technologies and central scientific concepts.After the RNA world hypothesis was proposed and developed,novel biological functions of RNA continue to be discovered.RNA and its related elements are widely used in many fields such as metabolic engineering and medical diagnosis,and their versatility led to a major role of RNA in synthetic biology.Further development of RNA-based technologies will advance synthetic biological tools as well as provide verification of the RNA world hypothesis.Most synthetic biology efforts are based on reconstructing existing biological systems,understanding fundamental biological processes,and developing new technologies.RNA-based technologies derived from phages will offer abundant sources for synthetic biological components.Moreover,phages as well as RNA have high impact on biological evolution,which is pivotal for understanding the origin of life,building artificial life-forms,and precisely reprogramming biological systems.This review discusses phage-derived RNA-based technologies terms of phage components,the phage lifecycle,and interactions between phages and bacteria.The significance of RNA-based technology derived from phages for synthetic biology and for understanding the earliest stages of biological evolution will be highlighted.
