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The G\u2010quadruplex (G4), a conserved regulatory element within viral genomes, represents a significant endogenous biomarker for tracking viral activity. However, imaging viral G4s in deep tissues remains a challenge for current optical technologies due to severe photon attenuation and autofluorescence. Herein, we report Lumin680, the first near\u2010infrared (NIR) chemiluminescent probe directly activated by conserved viral G4 conformations. Its chemiluminescence was triggered by parallel G4, emitting in the NIR optical window (680\u00a0nm) with a 104.6\u2010fold signal enhancement. Notably, the luminescence of Lumin680 could penetrate up to 1.2\u00a0cm of biological tissue, outperforming traditional G4 fluorescent probe. In vivo, Lumin680 enabled the rapid visualization of orthotopic hepatitis C virus (HCV) genome RNA\u2010presenting mini\u2010organ within 5 min post\u2010intravenous administration. Furthermore, the chemiluminescent intensity of Lumin680 quantitatively mapped the therapeutic efficacy of clinical direct\u2010acting antivirals (DAAs) at both the cellular and whole\u2010animal levels, exhibiting high concordance with the gold\u2010standard quantitative RT\u2010PCR (qPCR). This study not only provides a powerful G4 specific chemiluminescent tool but also establishes a novel paradigm for the non\u2010invasive, in situ diagnosis and precise therapeutic monitoring of viral infections.<\/jats:p>","DOI":"10.1002\/anie.7647795","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:23:33Z","timestamp":1783434213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A G\u2010Quadruplex\u2010Activated Near\u2010Infrared Chemiluminescent Probe for In Situ Hepatic Imaging of the Hepatitis C Virus Genome"],"prefix":"10.1002","volume":"65","author":[{"given":"Wen","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology Hunan University  Changsha P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Pathogenic Biology, Hainan Medical University\u2010The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, School of Basic Medical Sciences, Department of Clinical Laboratory of The Second Affiliated Hospital of Hainan Medical University, Hainan Academy of Medical Sciences Hainan Medical University  Hainan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Kuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology Hunan University  Changsha P. R. 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