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Herein, triple\u2010targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data\u2010driven design approach combined with a synthetic biology\u2010based assembly strategy, are introduced. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C\u2010X\u2010C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1), and vascular endothelial growth factor receptor 3 (VEGFR3) is identified, leveraging machine leaning\u2010based bioinformatics analysis and examination of LN tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage\u2010based nanoprobes capable of specifically binding to all three targets are designed through the self\u2010assembly of genetically engineered ferritin subunits using a synthetic biology approach. Using these nanoprobes, multiplexed imaging of heterogeneous metastatic LNs is successfully achieved in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple\u2010targeted nanoprobes significantly differentiates metastatic LNs from benign LNs. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis.<\/jats:p>","DOI":"10.1002\/adma.202405877","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T19:54:14Z","timestamp":1718740454000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Data\u2010Driven Design of Triple\u2010Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis"],"prefix":"10.1002","volume":"36","author":[{"given":"Guodong","family":"Shen","sequence":"first","affiliation":[{"name":"Department of General Surgery Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor Nanfang Hospital Southern Medical University  Guangzhou 510515 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