Leveraging bacteria for cancer immunotherapy has gradually attracted wide attention since the discovery of“Cloey’s toxin.”However,one of the persistent challenges for bacteria-based therapy is striking a balance be...Leveraging bacteria for cancer immunotherapy has gradually attracted wide attention since the discovery of“Cloey’s toxin.”However,one of the persistent challenges for bacteria-based therapy is striking a balance between safety and immunogenicity.Genetically engineered bacteria with virulence factors removed could further enhance antitumor ability by integrating genetic elements.In addition,bacterial derivatives,including outer membrane vesicles(OMVs)produced by bacterial secretion and nanovesicles synthesized by modification of OMVs,could enhance antitumor immunity while improving safety.This perspective discusses the unique advantages of engineered bacteria and their derivatives for immunotherapy,as well as the challenges that need to be overcome to achieve clinical translation.展开更多
In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless re...In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless revealed a tantalizing truth:The immune system,when properly provoked,could attack cancer.Over a century later,researchers have transformed this observation into a precision strike force.展开更多
Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefo...Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.展开更多
In Rhodopseudomonas palustris,an arsM gene,encoding bacterial and archaeal homologues of the mammalian Cyt19 As（III） S-adenosylmethionine methytransferase,was regulated by arsenicals.An expression of arsM was introd...In Rhodopseudomonas palustris,an arsM gene,encoding bacterial and archaeal homologues of the mammalian Cyt19 As（III） S-adenosylmethionine methytransferase,was regulated by arsenicals.An expression of arsM was introduced into strains for the methylation of arsenic.When arsM was expressed in Sphingomonas desiccabilis and Bacillus idriensis,it had 10 folds increase of methyled arsenic gas compared to wild type in aqueous system.In soil system,about 2.2%–4.5% of arsenic was removed by biovolatilization during 30 days.This study demonstrated that arsenic could be removed through volatilization from the contaminated soil by bacteria which have arsM gene expressed.These results showed that it is possible to use microorganisms expressing arsM as an inexpensive,efficient strategy for arsenic bioremediation from contaminated water and soil.展开更多
Nuclear safety is a global growing concern,where ionizing radiation(IR)is a major injury factor resulting in serious damage to organisms.The detection of IR is usually conducted with physical dosimeters;however,biolog...Nuclear safety is a global growing concern,where ionizing radiation(IR)is a major injury factor resulting in serious damage to organisms.The detection of IR is usually conducted with physical dosimeters;however,biological IR detection methods are deficient.Here,a living composite hydrogel consisting of engineered bacteria and gelatin/sodium alginate was 3D-printed for the biological detection of IR.Three strains of PrecA::egfp gene circuit-containing engineered Escherichia coli were constructed with IR-dependent fluorescence,and the DH5αstrain was finally selected due to its highest radiation response and fluorescence.Engineered bacteria were loaded in a series of gelatin/sodium alginate matrix hydrogels with different rheology,3D printability and bacterial applicability.A high-gelatin-content hydrogel containing 10%gelatin/1.25%sodium alginatewas optimal.The optimal living composite hydrogelwas 3D-printedwith the special bioink,which reported significant green fluorescence underγ-ray radiation.The living composite hydrogel provides a biological strategy for the detection of environmental ionizing radiation.展开更多
Cancer therapy remains a critical medical challenge.Immunotherapy is an emerging approach to regulating the immune system to fight cancer and has shown therapeutic potential.Due to their immunogenicity,bacteria have b...Cancer therapy remains a critical medical challenge.Immunotherapy is an emerging approach to regulating the immune system to fight cancer and has shown therapeutic potential.Due to their immunogenicity,bacteria have been developed as drug-delivery vehicles in cancer immunotherapy.However,ensuring the safety and efficacy of this approach poses a considerable challenge.This paper comprehensively explains the fundamental processes and synthesis principles involved in immunotherapy utilizing engineered bacteria.Initially,we list common engineered strains and discuss that growth control through genetic mutation promises therapeutic safety.By considering the characteristics of the tumor microenvironment and the interaction of specific molecules,the precision targeting of tumors can be improved.Furthermore,we present a foundational paradigm for genetic circuit construction to achieve controlled gene activation and logical expression,directly determining drug synthesis and release.Finally,we review the immunogenicity,the expression of immunomodulatory factors,the delivery of immune checkpoint inhibitors,and the utilization of bacteria as tumor vaccines to stimulate the immune system and facilitate the efficacy of cancer immunotherapy.展开更多
Adoptive cell therapy with chimeric antigen receptor(CAR)immunotherapy has demonstrated remarkable potential for hematologic malignancy while encountering challenges in extending the responsive list to solid tumors.Th...Adoptive cell therapy with chimeric antigen receptor(CAR)immunotherapy has demonstrated remarkable potential for hematologic malignancy while encountering challenges in extending the responsive list to solid tumors.The major hurdles include a lack of tumor-specific targets,inefficient trafficking,and tumor infiltration of the immune effector cells,along with their dysfunction and exhaustion in immune-suppressive tumor microenvironment(TME)1.Bacteria-mediated cancer immunotherapies(BCITs)have made remarkable progress in cancer immunotherapy over the past two decades.展开更多
Methicillin-resistant Staphylococcus aureus(MRSA)presents a significant challenge in wound infection treatment due to its antibiotic resistance and biofilm formation.To address this,we utilized Escherichia coli(Ec)as ...Methicillin-resistant Staphylococcus aureus(MRSA)presents a significant challenge in wound infection treatment due to its antibiotic resistance and biofilm formation.To address this,we utilized Escherichia coli(Ec)as a carrier to deliver lysozyme(LYZ)and adsorb the photosensitizer indocyanine green(ICG),resulting in the Ec-LYZ-ICG multi-functional antimicrobial platform.Since both Ec and MRSA are bacteria,this platform can act as a“spy”,evading the immune surveillance of MRSA and effectively penetrating infection sites.Upon exposure to 808 nm laser irradiation,Ec-LYZ-ICG utilizes the synergistic effects of photothermal therapy(PTT)and photodynamic therapy(PDT)induced by ICG,which ruptures Ec membrane and releases LYZ.The combined PTT and PDT directly damage MRSA,while LYZ further hydrolyzes MRSA.This strategy,with its“spy-like”camouflage and penetration abilities,overcomes MRSA’s antibiotic resistance and immune evasion,providing new insights and approaches for the precise treatment of MRSA infections.展开更多
The unique physiological characteristics and complexity of tumor,in addition to drug resistance result in traditional therapies,such as chemotherapy and radiotherapy,being unable to achieve complete elimination of can...The unique physiological characteristics and complexity of tumor,in addition to drug resistance result in traditional therapies,such as chemotherapy and radiotherapy,being unable to achieve complete elimination of cancer cells.Meanwhile,the emerging immunotherapy suffers from a low patient response rate.Bacterial therapies are highly targeted.Bacteria can penetrate deep into the tumor and show good tumor inhibition.However,natural bacteria have the limitation of high toxicity and inability to meet the demand for efficient therapeutics.Recent advances in synthetic biology and materials science relate to the safety and efficacy of bacterial therapeutics,promising to develop engineered bacteria with low toxicity and complex therapeutic functions.Engineered bacteria that express anticancer drug molecules can target the tumor region,synthesizing and releasing payloads in response to internal and external stimuli.This process leads to the regression of the tumor and the effective inhibition of recurrence.This review outlines the recent advancements in the field of engineered bacteria research,particularly focusing on their applications in anti-tumor therapy.It also includes the advantageous features and mechanisms of engineered bacteria therapy,synthetic biology modification methods,and future challenges and directions of engineered bacteria therapy.展开更多
Inflammatory bowel disease(IBD)is a chronic and recurrent disease caused by immune response disorders that disrupt the intestinal lumen symbiotic ecosystem and dysregulate mucosal immune functions.Current therapies av...Inflammatory bowel disease(IBD)is a chronic and recurrent disease caused by immune response disorders that disrupt the intestinal lumen symbiotic ecosystem and dysregulate mucosal immune functions.Current therapies available for IBD primarily focus on symptom management,making early diagnosis and prompt intervention challenging.The development of genetically engineered bacteria using synthetic biology presents a new strategy for addressing these challenges.In this review,we present recent breakthroughs in the field of engineered bac-teria for the treatment and detection of IBD and describe how bacteria can be genetically modified to produce therapeutic molecules or execute diagnostic functions.In particular,we discuss the challenges faced in translating live bacterial therapeutics from bacterial design to delivery strategies for further clinical applications.展开更多
Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics.It has made significant progress in breaking the limitat...Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics.It has made significant progress in breaking the limitations of monotherapy and effectively eradicating tumors,especially when combined with traditional therapy,such as radiotherapy.According to their different biological characteristics,bacteria and their derivatives can not only improve the sensitivity of tumor radiotherapy but also protect normal tissues.Moreover,genetically engineered bacteria and bacteria-based biomaterials have further expanded the scope of their applications in radiotherapy.In this review,we have summarized relevant researches on the application of bacteria and its derivatives in radiotherapy in recent years,expounding that the bacteria,bacterial derivatives and bacteria-based biomaterials can not only directly enhance radiotherapy but also improve the anti-tumor effect by improving the tumor microenvironment(TME)and immune effects.Furthermore,some probiotics can also protect normal tissues and organs such as intestines from radiation via anti-inflammatory,anti-oxidation and apoptosis inhibition.In conclusion,the prospect of bacteria in radiotherapy will be very extensive,but its biological safety and mechanism need to be further evaluated and studied.展开更多
Atherosclerotic plaques develop within the arterial intima,where rapid blood flow and high shear stress pose significant barriers to the adhesion of drug carriers to endothelial cells and their accumulation within pla...Atherosclerotic plaques develop within the arterial intima,where rapid blood flow and high shear stress pose significant barriers to the adhesion of drug carriers to endothelial cells and their accumulation within plaques.To overcome these challenges,we developed a genetically engineered anaerobic bacterium,Shewanella oneidensis MR-1,harboring a plasmid encoding hirudin-a potent thrombin inhibitor-and green fluorescent protein(GFP).Notably,this system retains the intrinsic hypoxia-targeting capability of Shewanella oneidensis MR-1 and is designed to selectively release hirudin-loaded vesicles in response to the acidic microenvironment within plaques.These bioengineered vesicles enable site-specific drug release,promoting localized accumulation at the lesion.The released hirudin effectively dissolves thrombi embedded within vulnerable plaques and modulates foam cell metabolism,thereby attenuating plaque progression.Our results demonstrate that the SO@AHG system offers a novel and precise therapeutic strategy for atherosclerosis,and highlights the potential of bacteria-mediated targeted delivery for cardiovascular disease treatment.展开更多
The development of drug delivery vehicles is in significant demand in the context of precision medicine.With the development of synthetic biology,the use of genetically engineered bacteria as drug delivery vectors has...The development of drug delivery vehicles is in significant demand in the context of precision medicine.With the development of synthetic biology,the use of genetically engineered bacteria as drug delivery vectors has attracted more and more attention.Herein,we reviewed the research advances in bioengineered bacteria as drug carriers,with emphasis on the synthetic biology strategies for modifying these bacteria,including the targeted realization method of engineered bacteria,the designing scheme of genetic circuits,and the release pathways of therapeutic compounds.Based on this,the essential components,design principles,and health concerns of engineering bacteria as drug carriers and the development prospects in this field have been discussed.展开更多
Conventional photodynamic therapy(PDT)approaches face challenges including limited light penetration,low uptake of photosensitizers by tumors,and lack of oxygen in tumor microenvironments.One promising solution is to ...Conventional photodynamic therapy(PDT)approaches face challenges including limited light penetration,low uptake of photosensitizers by tumors,and lack of oxygen in tumor microenvironments.One promising solution is to internally generate light,photosensitizers,and oxygen.This can be accomplished through endogenous production,such as using bioluminescence as an endogenous light source,synthesizing genetically encodable photosensitizers in situ,and modifying cells genetically to express catalase enzymes.Furthermore,these strategies have been reinforced by the recent rapid advancements in synthetic biology.In this review,we summarize and discuss the approaches to overcome PDT obstacles by means of endogenous production of excitation light,photosensitizers,and oxygen.We envision that as synthetic biology advances,genetically engineered cells could act as precise and targeted“living factories”to produce PDT components,leading to enhanced performance of PDT.展开更多
Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous stud...Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.展开更多
Cooperation is ubiquitous in biological sys- tems. However, if natural selection favors traits that confer an advantage to one individual over another, then helping others would be paradoxical. Nevertheless, cooperati...Cooperation is ubiquitous in biological sys- tems. However, if natural selection favors traits that confer an advantage to one individual over another, then helping others would be paradoxical. Nevertheless, cooperation persists and is critical in maintaining homeostasis in systems ranging from populations of bacteria to groupings of mammals. Developing an understanding of the dynamics and mechanisms by which cooperation operates is critical in understanding ecological and evolutionary relationships. Over the past decade, synthetic biology has emerged as a powerful tool to study social dynamics. By engineering rationally controlled and modulatable beha- vior into microbes, we have increased our overall under- standing of how cooperation enhances, or conversely constrains, populations. Furthermore, it has increased our understanding of how cooperation is maintained within populations, which may provide a useful framework to influence populations by altering cooperation. As many bacterial pathogens require cooperation to infect the host and survive, the principles developed using synthetic biology offer promise of developing novel tools and strategies to treat infections, which may reduce the use of antimicrobial agents. Overall, the use of engineered cooperative microbes has allowed the field to verify existing, and develop novel, theories that may govern cooperative behaviors at all levels of biology.展开更多
基金supported by the National Natural Science Foundation of China(nos.82222035 and 82372106)the Shenzhen Medical Research Found(no.B2302041).
文摘Leveraging bacteria for cancer immunotherapy has gradually attracted wide attention since the discovery of“Cloey’s toxin.”However,one of the persistent challenges for bacteria-based therapy is striking a balance between safety and immunogenicity.Genetically engineered bacteria with virulence factors removed could further enhance antitumor ability by integrating genetic elements.In addition,bacterial derivatives,including outer membrane vesicles(OMVs)produced by bacterial secretion and nanovesicles synthesized by modification of OMVs,could enhance antitumor immunity while improving safety.This perspective discusses the unique advantages of engineered bacteria and their derivatives for immunotherapy,as well as the challenges that need to be overcome to achieve clinical translation.
文摘In 1891,a New York surgeon named William Coley injected cancer patients with live bacteria,observing with fascination as some tumors shrank amid raging fevers.His crude experiments-later deemed reckless-nonetheless revealed a tantalizing truth:The immune system,when properly provoked,could attack cancer.Over a century later,researchers have transformed this observation into a precision strike force.
基金supported by the Science and Technology Research Project of Jilin Education Bureau(No.JJKH20230804KJ)。
文摘Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.
基金supported by the National Natural Science Foundation of China (No.40973058)the Ministry of Science and Technology (No.2007CB407304)
文摘In Rhodopseudomonas palustris,an arsM gene,encoding bacterial and archaeal homologues of the mammalian Cyt19 As（III） S-adenosylmethionine methytransferase,was regulated by arsenicals.An expression of arsM was introduced into strains for the methylation of arsenic.When arsM was expressed in Sphingomonas desiccabilis and Bacillus idriensis,it had 10 folds increase of methyled arsenic gas compared to wild type in aqueous system.In soil system,about 2.2%–4.5% of arsenic was removed by biovolatilization during 30 days.This study demonstrated that arsenic could be removed through volatilization from the contaminated soil by bacteria which have arsM gene expressed.These results showed that it is possible to use microorganisms expressing arsM as an inexpensive,efficient strategy for arsenic bioremediation from contaminated water and soil.
基金supported by the Special Program for Capability Promotion
文摘Nuclear safety is a global growing concern,where ionizing radiation(IR)is a major injury factor resulting in serious damage to organisms.The detection of IR is usually conducted with physical dosimeters;however,biological IR detection methods are deficient.Here,a living composite hydrogel consisting of engineered bacteria and gelatin/sodium alginate was 3D-printed for the biological detection of IR.Three strains of PrecA::egfp gene circuit-containing engineered Escherichia coli were constructed with IR-dependent fluorescence,and the DH5αstrain was finally selected due to its highest radiation response and fluorescence.Engineered bacteria were loaded in a series of gelatin/sodium alginate matrix hydrogels with different rheology,3D printability and bacterial applicability.A high-gelatin-content hydrogel containing 10%gelatin/1.25%sodium alginatewas optimal.The optimal living composite hydrogelwas 3D-printedwith the special bioink,which reported significant green fluorescence underγ-ray radiation.The living composite hydrogel provides a biological strategy for the detection of environmental ionizing radiation.
基金supported by National Key Research and Development Program of China(2023YFC3402600)National Natural Science Foundation of China(W2411072 and 82402460)Sanming Project of Medicine in Shenzhen(SZSM202111011).
文摘Cancer therapy remains a critical medical challenge.Immunotherapy is an emerging approach to regulating the immune system to fight cancer and has shown therapeutic potential.Due to their immunogenicity,bacteria have been developed as drug-delivery vehicles in cancer immunotherapy.However,ensuring the safety and efficacy of this approach poses a considerable challenge.This paper comprehensively explains the fundamental processes and synthesis principles involved in immunotherapy utilizing engineered bacteria.Initially,we list common engineered strains and discuss that growth control through genetic mutation promises therapeutic safety.By considering the characteristics of the tumor microenvironment and the interaction of specific molecules,the precision targeting of tumors can be improved.Furthermore,we present a foundational paradigm for genetic circuit construction to achieve controlled gene activation and logical expression,directly determining drug synthesis and release.Finally,we review the immunogenicity,the expression of immunomodulatory factors,the delivery of immune checkpoint inhibitors,and the utilization of bacteria as tumor vaccines to stimulate the immune system and facilitate the efficacy of cancer immunotherapy.
基金supported by grants from the National Key R&D Program of China(2022YFB3808100 and 2021YFA0909900,Xiao Zhao)the National Natural Science Foundation of China(32222045 and 32171384,Xiao Zhao)High Level Chinese Medical Hospital Promotion Project(HLCMHPP2023001,HLCMHPP2023097,and HLCMHPP2023085,Jie Li).
文摘Adoptive cell therapy with chimeric antigen receptor(CAR)immunotherapy has demonstrated remarkable potential for hematologic malignancy while encountering challenges in extending the responsive list to solid tumors.The major hurdles include a lack of tumor-specific targets,inefficient trafficking,and tumor infiltration of the immune effector cells,along with their dysfunction and exhaustion in immune-suppressive tumor microenvironment(TME)1.Bacteria-mediated cancer immunotherapies(BCITs)have made remarkable progress in cancer immunotherapy over the past two decades.
基金supported by the National Key R&D Program of China(No.2020YFA0210800)the National Natural Science Foundation of China(Nos.22174019 and 82301093).
文摘Methicillin-resistant Staphylococcus aureus(MRSA)presents a significant challenge in wound infection treatment due to its antibiotic resistance and biofilm formation.To address this,we utilized Escherichia coli(Ec)as a carrier to deliver lysozyme(LYZ)and adsorb the photosensitizer indocyanine green(ICG),resulting in the Ec-LYZ-ICG multi-functional antimicrobial platform.Since both Ec and MRSA are bacteria,this platform can act as a“spy”,evading the immune surveillance of MRSA and effectively penetrating infection sites.Upon exposure to 808 nm laser irradiation,Ec-LYZ-ICG utilizes the synergistic effects of photothermal therapy(PTT)and photodynamic therapy(PDT)induced by ICG,which ruptures Ec membrane and releases LYZ.The combined PTT and PDT directly damage MRSA,while LYZ further hydrolyzes MRSA.This strategy,with its“spy-like”camouflage and penetration abilities,overcomes MRSA’s antibiotic resistance and immune evasion,providing new insights and approaches for the precise treatment of MRSA infections.
基金the National Natural Science Foundation of China(62375093 and 32422042)Technology Innovation Program of Hubei Province(2024BCB058)。
文摘The unique physiological characteristics and complexity of tumor,in addition to drug resistance result in traditional therapies,such as chemotherapy and radiotherapy,being unable to achieve complete elimination of cancer cells.Meanwhile,the emerging immunotherapy suffers from a low patient response rate.Bacterial therapies are highly targeted.Bacteria can penetrate deep into the tumor and show good tumor inhibition.However,natural bacteria have the limitation of high toxicity and inability to meet the demand for efficient therapeutics.Recent advances in synthetic biology and materials science relate to the safety and efficacy of bacterial therapeutics,promising to develop engineered bacteria with low toxicity and complex therapeutic functions.Engineered bacteria that express anticancer drug molecules can target the tumor region,synthesizing and releasing payloads in response to internal and external stimuli.This process leads to the regression of the tumor and the effective inhibition of recurrence.This review outlines the recent advancements in the field of engineered bacteria research,particularly focusing on their applications in anti-tumor therapy.It also includes the advantageous features and mechanisms of engineered bacteria therapy,synthetic biology modification methods,and future challenges and directions of engineered bacteria therapy.
基金This work was sponsored by the National Key Research and Devel-opment Program of China(2023YFF1204500)the National Natural Sci-ence Foundation of China(22134003)China Postdoctoral Science Foundation(2023M741176).
文摘Inflammatory bowel disease(IBD)is a chronic and recurrent disease caused by immune response disorders that disrupt the intestinal lumen symbiotic ecosystem and dysregulate mucosal immune functions.Current therapies available for IBD primarily focus on symptom management,making early diagnosis and prompt intervention challenging.The development of genetically engineered bacteria using synthetic biology presents a new strategy for addressing these challenges.In this review,we present recent breakthroughs in the field of engineered bac-teria for the treatment and detection of IBD and describe how bacteria can be genetically modified to produce therapeutic molecules or execute diagnostic functions.In particular,we discuss the challenges faced in translating live bacterial therapeutics from bacterial design to delivery strategies for further clinical applications.
基金partially supported by the National Natural Science Foundation of China(U1932208,32171382)Key Research and Development Program of Social Development of Jiangsu Province(BE2022725,China)+2 种基金Hui-Chun Chin and Tsung-Dao Lee Chinese Undergraduate Research Endowment(CURE,China)Undergraduate Training Program for Innovation and Entrepreneurship Soochow University(202010285046Z,China)the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,China)。
文摘Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics.It has made significant progress in breaking the limitations of monotherapy and effectively eradicating tumors,especially when combined with traditional therapy,such as radiotherapy.According to their different biological characteristics,bacteria and their derivatives can not only improve the sensitivity of tumor radiotherapy but also protect normal tissues.Moreover,genetically engineered bacteria and bacteria-based biomaterials have further expanded the scope of their applications in radiotherapy.In this review,we have summarized relevant researches on the application of bacteria and its derivatives in radiotherapy in recent years,expounding that the bacteria,bacterial derivatives and bacteria-based biomaterials can not only directly enhance radiotherapy but also improve the anti-tumor effect by improving the tumor microenvironment(TME)and immune effects.Furthermore,some probiotics can also protect normal tissues and organs such as intestines from radiation via anti-inflammatory,anti-oxidation and apoptosis inhibition.In conclusion,the prospect of bacteria in radiotherapy will be very extensive,but its biological safety and mechanism need to be further evaluated and studied.
基金supported by the National Natural Science Foundation of China(No.82104405),the Natural Science Foundation of Zhejiang Province(No.LY23H300002)the Funds of the Natural Science Foundation of Hangzhou under(No.2024SZRYBH160002)the Research Project of Zhejiang Chinese Medical University(Nos.2024JKZKTS24,and 2024FSYYZQ31).
文摘Atherosclerotic plaques develop within the arterial intima,where rapid blood flow and high shear stress pose significant barriers to the adhesion of drug carriers to endothelial cells and their accumulation within plaques.To overcome these challenges,we developed a genetically engineered anaerobic bacterium,Shewanella oneidensis MR-1,harboring a plasmid encoding hirudin-a potent thrombin inhibitor-and green fluorescent protein(GFP).Notably,this system retains the intrinsic hypoxia-targeting capability of Shewanella oneidensis MR-1 and is designed to selectively release hirudin-loaded vesicles in response to the acidic microenvironment within plaques.These bioengineered vesicles enable site-specific drug release,promoting localized accumulation at the lesion.The released hirudin effectively dissolves thrombi embedded within vulnerable plaques and modulates foam cell metabolism,thereby attenuating plaque progression.Our results demonstrate that the SO@AHG system offers a novel and precise therapeutic strategy for atherosclerosis,and highlights the potential of bacteria-mediated targeted delivery for cardiovascular disease treatment.
基金This work is supported by I-Corps at Ohio(No.UT22117).
文摘The development of drug delivery vehicles is in significant demand in the context of precision medicine.With the development of synthetic biology,the use of genetically engineered bacteria as drug delivery vectors has attracted more and more attention.Herein,we reviewed the research advances in bioengineered bacteria as drug carriers,with emphasis on the synthetic biology strategies for modifying these bacteria,including the targeted realization method of engineered bacteria,the designing scheme of genetic circuits,and the release pathways of therapeutic compounds.Based on this,the essential components,design principles,and health concerns of engineering bacteria as drug carriers and the development prospects in this field have been discussed.
基金supported by the National Natural Science Foundation of China(32000036)。
文摘Conventional photodynamic therapy(PDT)approaches face challenges including limited light penetration,low uptake of photosensitizers by tumors,and lack of oxygen in tumor microenvironments.One promising solution is to internally generate light,photosensitizers,and oxygen.This can be accomplished through endogenous production,such as using bioluminescence as an endogenous light source,synthesizing genetically encodable photosensitizers in situ,and modifying cells genetically to express catalase enzymes.Furthermore,these strategies have been reinforced by the recent rapid advancements in synthetic biology.In this review,we summarize and discuss the approaches to overcome PDT obstacles by means of endogenous production of excitation light,photosensitizers,and oxygen.We envision that as synthetic biology advances,genetically engineered cells could act as precise and targeted“living factories”to produce PDT components,leading to enhanced performance of PDT.
基金supported by the National Natural Science Foundation of China (82272811 and 81930080)the Fund for Distinguished Young Scholars of Jiangsu Province (BK20230001).
文摘Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.
文摘Cooperation is ubiquitous in biological sys- tems. However, if natural selection favors traits that confer an advantage to one individual over another, then helping others would be paradoxical. Nevertheless, cooperation persists and is critical in maintaining homeostasis in systems ranging from populations of bacteria to groupings of mammals. Developing an understanding of the dynamics and mechanisms by which cooperation operates is critical in understanding ecological and evolutionary relationships. Over the past decade, synthetic biology has emerged as a powerful tool to study social dynamics. By engineering rationally controlled and modulatable beha- vior into microbes, we have increased our overall under- standing of how cooperation enhances, or conversely constrains, populations. Furthermore, it has increased our understanding of how cooperation is maintained within populations, which may provide a useful framework to influence populations by altering cooperation. As many bacterial pathogens require cooperation to infect the host and survive, the principles developed using synthetic biology offer promise of developing novel tools and strategies to treat infections, which may reduce the use of antimicrobial agents. Overall, the use of engineered cooperative microbes has allowed the field to verify existing, and develop novel, theories that may govern cooperative behaviors at all levels of biology.
