As the central template for protein expression,messenger ribonucleic acid(mRNA)holds immense potential for novel therapeutic strategies.Over the past few decades,mRNA-based therapeutics have demonstrated remarkable ef...As the central template for protein expression,messenger ribonucleic acid(mRNA)holds immense potential for novel therapeutic strategies.Over the past few decades,mRNA-based therapeutics have demonstrated remarkable efficacy in a range of applications,including epidemic vaccine,cancer vaccine,protein replacement therapy,cytokine therapy,cell therapy and gene editing.Due to the inherent instability of mRNA,the rational design of mRNA structure is the prerequisite for therapeutic utility while effective delivery systems are also essential for in vivo applications.This review focuses on the optimization of mRNA structure and highlights key delivery strategies.It also provides a comprehensive overview of the major applications of mRNA-based strategies.In addition,it highlights the persistent challenges in m RNA therapeutics,particularly in terms of stability,immunogenicity,delivery efficiency and safety.By examining recent advances in mRNA design,delivery and application,this review aims to support ongoing research and development in the field of mRNA-based therapeutics.展开更多
Phosphatase and tensin homolog deleted on chromosome 10(PTEN)messenger RNA(mRNA)delivery has fueled a great hope for tumor immunotherapy via augmenting the immune sensitivity in many human cancers.However,therapeutic ...Phosphatase and tensin homolog deleted on chromosome 10(PTEN)messenger RNA(mRNA)delivery has fueled a great hope for tumor immunotherapy via augmenting the immune sensitivity in many human cancers.However,therapeutic efficacy and clinical translation are limited by inadequate mRNA expression,insufficient immune stimulation and stringent storage requirements.Herein,inspired by the intrinsic properties of metal ions and exosomes,we developed a biomimetic delivery system(Mn-NP@PM)with superior stability for precise colorectal cancer immunotherapy.This platform employs adjuvant-metal-ion chelation for PTEN mRNA loading and PD-L1 antibodies(αPD-L1)-modified monocyte-macrophage membrane coating for mRNA protection and tumor targeting.Mn^(2+) was specifically selected due to its capacity for reversible mRNA binding through weak non-electrostatic interactions,facilitating efficient release,while simultaneously activating the stimulator of interferon genes(STING)pathway.Importantly,Mn-NP@PM exhibited membrane fusion for immediate cytosolic mRNA delivery,bypassing endo-lysosomal escape,optimizing transportation efficiency.Clinical-data-driven analyses further demonstrated that Mn-NP@PM-mediated PTEN restoration significantly increased T-cell infiltration and strengthened antitumor immunity in humanized patient derived xenograft(PDX)models.Collectively,this biomimetic,metal-ion-chelating,membrane-coated mRNA delivery system represents a versatile and clinically translatable strategy for personalized cancer immunotherapy.展开更多
基金supported by the National Key Research and Development Program of China(No.2023YFA0915400)the National Natural Science Foundation of China(No.22277072,22407099 and 32401161)+3 种基金Shanghai Oriental Talents(QNWS2024055)Shanghai Municipal Science and Technology Commission(No.24ZR1462700)the Science and Technology Development Fund of Pudong Health Bureau of Shanghai(No.PKJ2024-Y40)“Clinic Plus”Outstanding Project(No.2021ZYB009 and No.2021ZYB003)from Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine,and Innovative research team of high-level local universities in Shanghai。
文摘As the central template for protein expression,messenger ribonucleic acid(mRNA)holds immense potential for novel therapeutic strategies.Over the past few decades,mRNA-based therapeutics have demonstrated remarkable efficacy in a range of applications,including epidemic vaccine,cancer vaccine,protein replacement therapy,cytokine therapy,cell therapy and gene editing.Due to the inherent instability of mRNA,the rational design of mRNA structure is the prerequisite for therapeutic utility while effective delivery systems are also essential for in vivo applications.This review focuses on the optimization of mRNA structure and highlights key delivery strategies.It also provides a comprehensive overview of the major applications of mRNA-based strategies.In addition,it highlights the persistent challenges in m RNA therapeutics,particularly in terms of stability,immunogenicity,delivery efficiency and safety.By examining recent advances in mRNA design,delivery and application,this review aims to support ongoing research and development in the field of mRNA-based therapeutics.
基金supported by the Basic Science Center Project of the National Natural Science Foundation of China(22388101)New Cornerstone Science Foundation(NCI202318)+6 种基金the National Natural Science Foundation of China(32171398 and T242200557)the National Key R&D Program of China(2023YFA1610200 and 2022YFA1603701)Beijing Nova Program(20220484060,20230484426,and 20240484661)Beijing Natural Science Foundation(F251001)Chinese Academy of Sciences Project for Young Scientists in Basic Research(YSBR-036)the One Hundred Talents Program of Chinese Academy of Sciences(E3G551R1ZX)Chinese Academy of Medical Sciences(CAMS)and Innovation Fund for Medical Sciences(CIFMS2019-I2M-5-018).
文摘Phosphatase and tensin homolog deleted on chromosome 10(PTEN)messenger RNA(mRNA)delivery has fueled a great hope for tumor immunotherapy via augmenting the immune sensitivity in many human cancers.However,therapeutic efficacy and clinical translation are limited by inadequate mRNA expression,insufficient immune stimulation and stringent storage requirements.Herein,inspired by the intrinsic properties of metal ions and exosomes,we developed a biomimetic delivery system(Mn-NP@PM)with superior stability for precise colorectal cancer immunotherapy.This platform employs adjuvant-metal-ion chelation for PTEN mRNA loading and PD-L1 antibodies(αPD-L1)-modified monocyte-macrophage membrane coating for mRNA protection and tumor targeting.Mn^(2+) was specifically selected due to its capacity for reversible mRNA binding through weak non-electrostatic interactions,facilitating efficient release,while simultaneously activating the stimulator of interferon genes(STING)pathway.Importantly,Mn-NP@PM exhibited membrane fusion for immediate cytosolic mRNA delivery,bypassing endo-lysosomal escape,optimizing transportation efficiency.Clinical-data-driven analyses further demonstrated that Mn-NP@PM-mediated PTEN restoration significantly increased T-cell infiltration and strengthened antitumor immunity in humanized patient derived xenograft(PDX)models.Collectively,this biomimetic,metal-ion-chelating,membrane-coated mRNA delivery system represents a versatile and clinically translatable strategy for personalized cancer immunotherapy.
