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通过多模块 DNA 纳米结构组装进行的 mRNA 区室化增强了癌症 mRNA 疫苗的免疫原性和疗效。

mRNA compartmentalization via multimodule DNA nanostructure assembly augments the immunogenicity and efficacy of cancer mRNA vaccine.

机构信息

New Cornerstone Science Laboratory, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China.

Health Management Institute, The Second Medical Center, Chinese PLA General Hospital, Beijing 100853, China.

出版信息

Sci Adv. 2024 Nov 22;10(47):eadp3680. doi: 10.1126/sciadv.adp3680.

DOI:10.1126/sciadv.adp3680
PMID:39576858
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11584007/
Abstract

Messenger RNA (mRNA) vaccine has fueled a great hope for cancer immunotherapy. However, low immunogenicity, caused by inefficient mRNA expression and weak immune stimulation, hampers the efficacy of mRNA vaccines. Here, we present an mRNA compartmentalization-based cancer vaccine, comprising a multimodule DNA nanostructure (MMDNS)-assembled compartment for efficient mRNA translation via in situ localizing mRNA concentration and relevant reaction molecules. The MMDNS is constructed via programmable DNA hybridization chain reaction (HCR)-based strategy, with integrating antigen-coded mRNA, CpG oligodeoxynucleotides (ODNs), acidic-responsive DNA sequence, and dendritic cells targeting aptamer. MMDNS undergoes in situ assembly in acidic lysosomes to form a micro-sized aggregate, inducing an enhanced CpG ODN adjuvant efficacy. Subsequently, the aggregates escape into cytoplasm, providing a moderate compartment which supports the efficient translation of spatially proximal mRNA transcripts via localizing relevant reaction molecules. The mRNA compartmentalization-based vaccine boosts a strong immune response and effectively inhibits tumor growth and metastasis, offering a robust strategy for cancer immunotherapy.

摘要

信使 RNA（mRNA）疫苗为癌症免疫疗法带来了巨大的希望。然而，mRNA 表达效率低下和免疫刺激较弱导致的低免疫原性，限制了 mRNA 疫苗的疗效。在这里，我们提出了一种基于 mRNA 区室化的癌症疫苗，它包含一个多模块 DNA 纳米结构（MMDNS）组装的区室，通过原位定位 mRNA 浓度和相关反应分子来实现高效的 mRNA 翻译。MMDNS 是通过可编程 DNA 杂交链式反应（HCR）为基础的策略构建的，整合了抗原编码的 mRNA、CpG 寡脱氧核苷酸（ODN）、酸性响应 DNA 序列和树突状细胞靶向适体。MMDNS 在酸性溶酶体中进行原位组装，形成微尺寸的聚集物，从而增强 CpG ODN 佐剂的效果。随后，这些聚集物逃逸到细胞质中，提供一个适度的区室，通过定位相关的反应分子来支持空间上邻近的 mRNA 转录的高效翻译。基于 mRNA 区室化的疫苗可引发强烈的免疫反应，有效抑制肿瘤生长和转移，为癌症免疫疗法提供了一种强大的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/900a/11584007/4faa96b054ef/sciadv.adp3680-f8.jpg
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