Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University, The Sixth People's Hospital of Nantong, School of Medicine, Shanghai University, Nantong 226011, P. R. China.
Center for Molecular Recognition and Biosensing, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, P. R. China.
J Am Chem Soc. 2022 Aug 3;144(30):13475-13486. doi: 10.1021/jacs.2c00119. Epub 2022 Jul 8.
Breast cancer is very heterogeneous and the most frequently diagnosed cancer worldwide, and precise therapy targeting specific subtypes may improve the survival rates of breast cancer patients. In this study, we designed a biomimetic vesicle by camouflaging catalytic DNA machinery with a breast cancer cell membrane, which enabled the molecular classification of circulating exosomes for subtype-based diagnosis through homotypic recognition. In addition, the vesicles specifically targeted and fused with breast cancer exosomes with phenotypic homology and manipulated the DNA machinery to amplify electrochemical signaling using exosomal RNA as an endogenous trigger. The biomimetic vesicles prepared with MCF-7 cancer cell-derived membranes were shown to recognize estrogen receptor-positive breast cancer exosomes and exhibited a low detection limit of 557 particles mL with microRNA-375 used as the endogenous biomarker. Furthermore, the biomimetic vesicles prepared with MDA-MB-231 cancer cell-derived membranes displayed satisfactory performance in a homotypic analysis of triple-negative breast cancer exosomes with a potential therapeutic target, PD-L1 mRNA, used as the endogenous biomarker. Most importantly, cross-validation experiments confirmed the high accuracy and selectivity of this homotypic recognition-driven analysis for molecular subtyping of breast cancer. When applied to clinical samples of breast cancer patients, the vesicles demonstrated feasibility and reliability for evaluating the molecular features of cancer cell-derived exosomes and enabled stage-specific monitoring of breast cancer patients because the electrochemical signals showed a positive correlation with disease progression. Therefore, this work may provide new ideas for the precise diagnosis and personalized treatment of breast cancer patients throughout the whole disease process.
乳腺癌具有高度异质性，是全球最常见的癌症，针对特定亚型的精准治疗可能会提高乳腺癌患者的生存率。在本研究中，我们设计了一种仿生囊泡，通过将催化 DNA 机器伪装成乳腺癌细胞膜，使循环外泌体能够通过同型识别进行基于亚型的诊断的分子分类。此外，这些囊泡特异性地靶向并融合具有表型同源性的乳腺癌外泌体，并利用外泌体 RNA 作为内源性触发物来操纵 DNA 机器以放大电化学生物信号。使用 MCF-7 癌细胞衍生的膜制备的仿生囊泡被证明可以识别雌激素受体阳性乳腺癌外泌体，并且使用 microRNA-375 作为内源性生物标志物，检测限低至 557 个颗粒/mL。此外，使用 MDA-MB-231 癌细胞衍生的膜制备的仿生囊泡在三阴性乳腺癌外泌体的同型分析中表现出令人满意的性能，其潜在治疗靶点 PD-L1 mRNA 被用作内源性生物标志物。最重要的是，交叉验证实验证实了这种同型识别驱动的分析对乳腺癌分子亚型的高准确性和选择性。当应用于乳腺癌患者的临床样本时，该囊泡表现出评估癌细胞衍生外泌体的分子特征的可行性和可靠性，并能够对乳腺癌患者进行特定阶段的监测，因为电化学生物信号与疾病进展呈正相关。因此，这项工作可能为乳腺癌患者在整个疾病过程中的精准诊断和个性化治疗提供新的思路。
