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
The"one drug-multiple targets"paradigm has revolutionized therapeutic development for complex diseases by addressing the limitations of single-target approaches[1].However,elucidating multi-target synergism ...The"one drug-multiple targets"paradigm has revolutionized therapeutic development for complex diseases by addressing the limitations of single-target approaches[1].However,elucidating multi-target synergism remains a major challenge.Network pharmacology(NP)enables polypharmacological investigations through biological networks[2].展开更多
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.
基金supported by the National Key R&D Program of China(2022YFF1203304)the National Natural Science Foundation of China(92474204,32070670,and 32341019)+5 种基金the Ningbo Top Medical and Health Research Program(2023030615 and 2024020919)the Beijing Natural Science Foundation Haidian Origination and Innovation Joint Fund(L222007)the Ningbo Science and Technology Innovation Yongjiang 2035 Project(2023Z226 and 2024Z229)the Major Project of Guangzhou National Laboratory(GZNL2023A03001)the Beijing Nova Program(20240484661)the State Key Laboratory of Systems Medicine for Cancer(KF2422-93).
文摘The"one drug-multiple targets"paradigm has revolutionized therapeutic development for complex diseases by addressing the limitations of single-target approaches[1].However,elucidating multi-target synergism remains a major challenge.Network pharmacology(NP)enables polypharmacological investigations through biological networks[2].
