Achieving robust and durable cellular immunity remains a key challenge in the development of subunit vaccines,primarily due to inefficient antigen cross-presentation and inadequate immune activation.Here,we engineered...Achieving robust and durable cellular immunity remains a key challenge in the development of subunit vaccines,primarily due to inefficient antigen cross-presentation and inadequate immune activation.Here,we engineered a series of nano-emulsions by conjugating human serum albumin(HSA)with fatty acids of varying chain lengths.Through systematic screening,the palmitic acid-modified nano-emulsion was identified as the most effective carrier,exhibiting intrinsic self-adjuvant properties and a strong capacity to elicit cellular immune responses.Notably,this formulation enables cascade-targeted delivery,trafficking sequentially from lymph nodes to antigen-presenting cells(APCs),and ultimately to the endoplasmic reticulum(ER).Upon co-delivery of the model antigen ovalbumin(OVA)and a stimulator of interferon genes(STING)agonist,the nano-emulsion fa-cilitates both efficient antigen cross-presentation and precise intracellular activation of the STING pathway.This synergistic mechanism significantly enhances CD8^(+)T cell responses and promotes durable memory formation,resulting in potent antitumor efficacy in murine models.Collectively,this study presents a safe and versatile nano-emulsion platform that overcomes key barriers in subunit vaccine delivery,offering a promising strategy for next-generation vaccine design.展开更多
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
基金supported by the National Natural Science Foundation of China(Grant No.82373799).
文摘Achieving robust and durable cellular immunity remains a key challenge in the development of subunit vaccines,primarily due to inefficient antigen cross-presentation and inadequate immune activation.Here,we engineered a series of nano-emulsions by conjugating human serum albumin(HSA)with fatty acids of varying chain lengths.Through systematic screening,the palmitic acid-modified nano-emulsion was identified as the most effective carrier,exhibiting intrinsic self-adjuvant properties and a strong capacity to elicit cellular immune responses.Notably,this formulation enables cascade-targeted delivery,trafficking sequentially from lymph nodes to antigen-presenting cells(APCs),and ultimately to the endoplasmic reticulum(ER).Upon co-delivery of the model antigen ovalbumin(OVA)and a stimulator of interferon genes(STING)agonist,the nano-emulsion fa-cilitates both efficient antigen cross-presentation and precise intracellular activation of the STING pathway.This synergistic mechanism significantly enhances CD8^(+)T cell responses and promotes durable memory formation,resulting in potent antitumor efficacy in murine models.Collectively,this study presents a safe and versatile nano-emulsion platform that overcomes key barriers in subunit vaccine delivery,offering a promising strategy for next-generation vaccine design.
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.
