Zijin Luo, Yi Lin, Yanan Meng, Mengyao Li, Hongyu Ren, Haoping Shi, Qiang Cheng, Tuo Wei
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引用次数: 0
Abstract
The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn2+) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.
mRNA 疫苗在预防和治疗传染病方面的成功应用凸显了其作为癌症治疗疫苗的潜力。然而,与传染病不同,有效的抗肿瘤治疗,尤其是实体瘤的治疗,必须激活更强大的细胞和体液免疫才能取得临床疗效。在这里,我们报告了一种脾脏靶向 mRNA 疫苗(Mn@mRNA-LNP),其设计目的是将肿瘤抗原编码的 mRNA 和锰佐剂(Mn2+)同时递送到脾脏的树突状细胞(DCs)。这种递送系统能促进 DC 成熟和表面抗原呈递,并刺激细胞毒性 T 细胞的产生。此外,该系统中编码递送的 Mn2+ 可作为一种安全有效的免疫佐剂,激活干扰素基因刺激器(STING)信号通路,促进 I 型干扰素的分泌,进一步增强抗原特异性 T 细胞反应。Mn@mRNA-LNP 能有效抑制已建立的黑色素瘤和结肠肿瘤模型以及切除后肿瘤复发模型中的肿瘤进展。值得注意的是,Mn@mRNA-LNP 与免疫检查点抑制剂的结合进一步增强了对肿瘤的完全抑制,并延长了小鼠的总体生存期。总之,这种 "一体化 "mRNA疫苗通过改善脾脏靶向性和免疫激活,显著提高了抗肿瘤免疫反应,为未来治疗性mRNA疫苗的临床转化提供了一种极具吸引力的策略。
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.