Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenv...Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment,in addition to improving oral bioavailability relative to other means of delivery of oral drugs.Here,inspired by the specific invasion route of intestinal microorganisms,we pioneered an immune-awakening Saccharomyces-inspired mesoporous silicon nanoparticle(yMSN)for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway.Encouragingly,yMSN high-loaded tumor-specific antigens(OVA,11.9%)and anti-tumor drugs(Len,28.6%)with high stability,namely Len/OVA/yMSN,efficiently co-delivered OVA and Len to their desired target sites.Moreover,yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages,strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment.Surprisingly,Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice.This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment,and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.展开更多
Background:Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment.Our previous clinical trial demonstrated that berberine(BBR)hydrochloride might reduce the r...Background:Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment.Our previous clinical trial demonstrated that berberine(BBR)hydrochloride might reduce the recurrence and canceration of colorectal adenoma(CRA).The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer(CRC).Methods:We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial,and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction.We further performed Apc Min/+animal intervention tests,RNA sequencing,flow cytometry,immunohistochemistry,and enzyme-linked immunosorbent assays.Results:The abundance of fecal Veillonella parvula(V.parvula)decreased significantly after BBR administration(P=0.0016)and increased through the development from CRA to CRC.Patients with CRC with a higher V.parvula abundance had worse tumor staging and a higher lymph node metastasis rate.The intestinal immune pathway of Immunoglobulin A production was activated,and the expression of TNFSF13B(Tumor necrosis factor superfamily 13b,encoding B lymphocyte stimulator[BLyS]),the representative gene of this pathway,and the genes encoding its receptors(interleukin-10 and transforming growth factor beta)were significantly upregulated.Animal experiments revealed that V.parvula promoted colorectal carcinogenesis and increased BLyS levels,while BBR reversed this effect.Conclusion:BBR might inhibit V.parvula and further weaken the immunomodulatory effect of B cells induced by V.parvula,thereby blocking the development of colorectal tumors.Trial Registraion:ClinicalTrials.gov,No.NCT02226185.展开更多
基金This work was supported by China Postdoctoral Science Foundation(No.2020T130434,China)National Natural Science Foundation of China(No.82073798,China)+2 种基金National Natural Science Foundation of China(No.82104107,China)National Basic Research Program of China(973 Program)(No.2015CB932100,China)Doctoral Start-up Foundation of Liaoning Province(No.2021-BS-127,China).
文摘Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment,in addition to improving oral bioavailability relative to other means of delivery of oral drugs.Here,inspired by the specific invasion route of intestinal microorganisms,we pioneered an immune-awakening Saccharomyces-inspired mesoporous silicon nanoparticle(yMSN)for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway.Encouragingly,yMSN high-loaded tumor-specific antigens(OVA,11.9%)and anti-tumor drugs(Len,28.6%)with high stability,namely Len/OVA/yMSN,efficiently co-delivered OVA and Len to their desired target sites.Moreover,yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages,strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment.Surprisingly,Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice.This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment,and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.
基金supported by the grants from the National Key R&D Program of China(No.2020YFA0509200)the National Natural Science Foundation of China(Nos.82002622,81830081,31970718,and 81972203)+1 种基金the Shanghai Municipal Health Commission,Collaborative Innovation Cluster Project(No.2019CXJQ02)the Youth Project of Shanghai Municipal Health Commission(No.20194Y0096)
文摘Background:Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment.Our previous clinical trial demonstrated that berberine(BBR)hydrochloride might reduce the recurrence and canceration of colorectal adenoma(CRA).The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer(CRC).Methods:We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial,and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction.We further performed Apc Min/+animal intervention tests,RNA sequencing,flow cytometry,immunohistochemistry,and enzyme-linked immunosorbent assays.Results:The abundance of fecal Veillonella parvula(V.parvula)decreased significantly after BBR administration(P=0.0016)and increased through the development from CRA to CRC.Patients with CRC with a higher V.parvula abundance had worse tumor staging and a higher lymph node metastasis rate.The intestinal immune pathway of Immunoglobulin A production was activated,and the expression of TNFSF13B(Tumor necrosis factor superfamily 13b,encoding B lymphocyte stimulator[BLyS]),the representative gene of this pathway,and the genes encoding its receptors(interleukin-10 and transforming growth factor beta)were significantly upregulated.Animal experiments revealed that V.parvula promoted colorectal carcinogenesis and increased BLyS levels,while BBR reversed this effect.Conclusion:BBR might inhibit V.parvula and further weaken the immunomodulatory effect of B cells induced by V.parvula,thereby blocking the development of colorectal tumors.Trial Registraion:ClinicalTrials.gov,No.NCT02226185.
