Controllable targeted protein degradation(controllable TPD)technologies,exemplified by proteolysis-targeting chimeras(PROTACs),have emerged as transformative tools in drug discovery and molecular biology research.With...Controllable targeted protein degradation(controllable TPD)technologies,exemplified by proteolysis-targeting chimeras(PROTACs),have emerged as transformative tools in drug discovery and molecular biology research.With the endogenous cellular degradation machinery,controllable TPD platforms allow for the precise targeting and regulated elimination of specific proteins within cells.Recent advances have expanded the spectrum of controllable degradation strategies,including photosensitive degrons,opto-PROTACs,auxin-inducible degron(AID)systems,small molecule-assisted shut-off(SMASh)techniques,and engineered E3 ubiquitin ligases such as ΔTRIM21 with enhanced targeted protein degradation efficiency(ΔTRIM-TPD).These emerging methodologies provide unprecedented control over protein stability,facilitating targeted therapeutic interventions for diseases such as cancer and infectious diseases,and significantly advancing fundamental biological research.This review systematically summarizes recent breakthroughs in controllable TPD strategies,elucidates their distinct molecular mechanisms,and highlights their promising therapeutic applications.The rapidly evolving field of controllable TPD represents a powerful and adaptable technological frontier,opening new avenues in precision medicine and providing versatile tools for the future of biomedical research.展开更多
In the field of reproductive medicine,delaying ovarian aging and preserving fertility in cancer patients have long been core issues and relentless pursuits.Female germline stem cells(FGSCs)have been shown to repair ag...In the field of reproductive medicine,delaying ovarian aging and preserving fertility in cancer patients have long been core issues and relentless pursuits.Female germline stem cells(FGSCs)have been shown to repair aging or damaged ovarian structures and to restore ovarian reproductive and endocrine function.With their unlimited proliferation and directed differentiation into oocytes,FGSCs bring new hope to patients with ovarian insufficiency,malignant tumors,and others needing fertility preservation.In this review,we introduce the role of FGSCs in ovarian fertility preservation and regenerative repair,emphasizing the regulatory pathways of FGSCs in restoring ovarian function.We discuss the unique advantages of FGSCs in infertility treatment,including fertility preservation,animal gene editing,and regenerative medicine.This article aims to offer new research insights for advancing the clinical translation of FGSCs by exploring them from multiple perspectives,such as origin,regulation,and application.展开更多
Background： Recently, optogenetics based on genetically encoded photosensitive proteins has emerged as an innovative technology platform to revolutionize manipulation of cellular behavior through fight stimulation. I...Background： Recently, optogenetics based on genetically encoded photosensitive proteins has emerged as an innovative technology platform to revolutionize manipulation of cellular behavior through fight stimulation. It has enabled user defined control of various cellular behaviors with spatiotemporal precision and minimal invasiveness, creating unprecedented opportunities for biomedical applications. Results： This article reviews current advances in optogenetic networks designed for the treatment of human diseases. We highlight the advantages of these optogenetic networks, as well as emerging questions and future perspectives. Conclusions： Various optogenetic systems have been engineered to control biological processes at all levels using light and applied for numerous diseases, such as metabolic disorders, cancer, and immune diseases. Continued development of optogenetic modules will be necessary to precisely control of gene expression magnitude towards clinical medical practice in the context of real-world problems.展开更多
The ability to precisely control activities of engineered designer cells provides a novel strategy for modern precision medicine.Dynamically adjustable gene-and cell-based precision therapies are recognized as next ge...The ability to precisely control activities of engineered designer cells provides a novel strategy for modern precision medicine.Dynamically adjustable gene-and cell-based precision therapies are recognized as next generation medicines.However,the translation of these controllable therapeutics into clinical practice is severely hampered by the lack of safe and highly specific genetic switches controlled by triggers that are nontoxic and side-effect free.Recently,natural products derived from plants have been extensively explored as trigger molecules to control genetic switches and synthetic gene networks for multiple applications.These controlled genetic switches could be further introduced into mammalian cells to obtain synthetic designer cells for adjustable and fine tunable cell-based precision therapy.In this review,we introduce various available natural molecules that were engineered to control genetic switches for controllable transgene expression,complex logic computation,and therapeutic drug delivery to achieve precision therapy.We also discuss current challenges and prospects in translating these natural molecule-controlled genetic switches developed for biomedical applications from the laboratory to the clinic.展开更多
Diabetes treatment and rehabilitation are usually a lifetime process.Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis.However,portable,sustainable,and long-term ...Diabetes treatment and rehabilitation are usually a lifetime process.Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis.However,portable,sustainable,and long-term energy supplementation has previously presented a challenge for the use of optogenetic stimulation in vivo.Herein,we_purpose a self-powered optogenetic system(SOS)for implantable blood glucose control.The SOS consists of a biocompatible far-red light(FRL)source,FRL-triggered transgene-expressing cells,a power management unit,and a flexible implantable piezoelectric nanogenerator(i-PENG)to supply long-term energy by converting biomechanical energy into electricity.Our results show that this system can harvest energy from body movement and power the FRL source,which then significantly enhanced production of a short variant of human glucagon-like peptide 1(shGLP-1)in vitro and in vivo.Indeed,diabetic mice equipped with the SOS showed rapid restoration of blood glucose homeostasis,improved glucose,and insulin tolerance.Our results suggest that the SOs is sufficiently effective in self-powering the modulation of therapeutic outputs to control glucose homeostasis and,furthermore,present a new strategy for providing energy in optogenetic-based cell therapy.展开更多
基金supported by the National Natural Science Foundation of China(32430064,32250010)the Science and Technology Commission of Shanghai Municipality(23HC1410100,22N31900300)。
文摘Controllable targeted protein degradation(controllable TPD)technologies,exemplified by proteolysis-targeting chimeras(PROTACs),have emerged as transformative tools in drug discovery and molecular biology research.With the endogenous cellular degradation machinery,controllable TPD platforms allow for the precise targeting and regulated elimination of specific proteins within cells.Recent advances have expanded the spectrum of controllable degradation strategies,including photosensitive degrons,opto-PROTACs,auxin-inducible degron(AID)systems,small molecule-assisted shut-off(SMASh)techniques,and engineered E3 ubiquitin ligases such as ΔTRIM21 with enhanced targeted protein degradation efficiency(ΔTRIM-TPD).These emerging methodologies provide unprecedented control over protein stability,facilitating targeted therapeutic interventions for diseases such as cancer and infectious diseases,and significantly advancing fundamental biological research.This review systematically summarizes recent breakthroughs in controllable TPD strategies,elucidates their distinct molecular mechanisms,and highlights their promising therapeutic applications.The rapidly evolving field of controllable TPD represents a powerful and adaptable technological frontier,opening new avenues in precision medicine and providing versatile tools for the future of biomedical research.
基金supported by the National Natural Science Foundation of China 82402919.
文摘In the field of reproductive medicine,delaying ovarian aging and preserving fertility in cancer patients have long been core issues and relentless pursuits.Female germline stem cells(FGSCs)have been shown to repair aging or damaged ovarian structures and to restore ovarian reproductive and endocrine function.With their unlimited proliferation and directed differentiation into oocytes,FGSCs bring new hope to patients with ovarian insufficiency,malignant tumors,and others needing fertility preservation.In this review,we introduce the role of FGSCs in ovarian fertility preservation and regenerative repair,emphasizing the regulatory pathways of FGSCs in restoring ovarian function.We discuss the unique advantages of FGSCs in infertility treatment,including fertility preservation,animal gene editing,and regenerative medicine.This article aims to offer new research insights for advancing the clinical translation of FGSCs by exploring them from multiple perspectives,such as origin,regulation,and application.
文摘Background： Recently, optogenetics based on genetically encoded photosensitive proteins has emerged as an innovative technology platform to revolutionize manipulation of cellular behavior through fight stimulation. It has enabled user defined control of various cellular behaviors with spatiotemporal precision and minimal invasiveness, creating unprecedented opportunities for biomedical applications. Results： This article reviews current advances in optogenetic networks designed for the treatment of human diseases. We highlight the advantages of these optogenetic networks, as well as emerging questions and future perspectives. Conclusions： Various optogenetic systems have been engineered to control biological processes at all levels using light and applied for numerous diseases, such as metabolic disorders, cancer, and immune diseases. Continued development of optogenetic modules will be necessary to precisely control of gene expression magnitude towards clinical medical practice in the context of real-world problems.
基金the National Natural Science Foundation of China(NSFC:no.32250010,no.31971346,no.32261160373)the Science and Technology Commission of Shanghai Municipality(no.22N31900300)the Fundamental Research Funds for the Central Universities to H.Y.
文摘The ability to precisely control activities of engineered designer cells provides a novel strategy for modern precision medicine.Dynamically adjustable gene-and cell-based precision therapies are recognized as next generation medicines.However,the translation of these controllable therapeutics into clinical practice is severely hampered by the lack of safe and highly specific genetic switches controlled by triggers that are nontoxic and side-effect free.Recently,natural products derived from plants have been extensively explored as trigger molecules to control genetic switches and synthetic gene networks for multiple applications.These controlled genetic switches could be further introduced into mammalian cells to obtain synthetic designer cells for adjustable and fine tunable cell-based precision therapy.In this review,we introduce various available natural molecules that were engineered to control genetic switches for controllable transgene expression,complex logic computation,and therapeutic drug delivery to achieve precision therapy.We also discuss current challenges and prospects in translating these natural molecule-controlled genetic switches developed for biomedical applications from the laboratory to the clinic.
基金We are grateful to all the laboratory members for their cooperation in this study.This work was financially supported by grants from the National Key R&D Program of China,Synthetic Biology Research(no.2019YFA0904500)the National Natural Science Foundation of China(nos.82102231,31971346,61875015,31861143016,U20A20390,11827803,and T2125003)+4 种基金the Science and Technology Commission of Shanghai Municipality(no.22N31900300)Beijing Natural Science Foundation(JQ20038,L212010)China Postdoctoral Science Foundation(2020M680302,2021T140041)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16021101)We also thank the ECNU Multifunctional Platform for Innovation(011)for supporting the murine experiments and the Instruments Sharing Platform of the School of Life Sciences,ECNU.
文摘Diabetes treatment and rehabilitation are usually a lifetime process.Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis.However,portable,sustainable,and long-term energy supplementation has previously presented a challenge for the use of optogenetic stimulation in vivo.Herein,we_purpose a self-powered optogenetic system(SOS)for implantable blood glucose control.The SOS consists of a biocompatible far-red light(FRL)source,FRL-triggered transgene-expressing cells,a power management unit,and a flexible implantable piezoelectric nanogenerator(i-PENG)to supply long-term energy by converting biomechanical energy into electricity.Our results show that this system can harvest energy from body movement and power the FRL source,which then significantly enhanced production of a short variant of human glucagon-like peptide 1(shGLP-1)in vitro and in vivo.Indeed,diabetic mice equipped with the SOS showed rapid restoration of blood glucose homeostasis,improved glucose,and insulin tolerance.Our results suggest that the SOs is sufficiently effective in self-powering the modulation of therapeutic outputs to control glucose homeostasis and,furthermore,present a new strategy for providing energy in optogenetic-based cell therapy.
