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Proximity labeling emerges as a powerful tool to dissect the secretome, yet conventional workflows typically rely on single\u2010compartment biotinylation at the endoplasmic reticulum (ER), failing to capture proteins that utilize unconventional secretion. Here, we present DuO\u2010SCOUT (Dual\u2010Organelle Secretome Conjugation and Organ\u2010Uptake Tracking), a high\u2010performance platform that simultaneously targets BioID2 to the ER and the trans\u2010Golgi network (TGN). This integrated strategy captures the full secretory maturation relay, increasing protein identification by over 120% compared to traditional ER\u2010anchored methods. We translated this in vivo using an Adipoq\u2010Cre mouse model to map the adipose secretome. To bridge the gap between systemic transport and tissue\u2010specific uptake, DuO\u2010SCOUT integrates BSPA (Biotin\u2010Specific Proximity Amplification), a visualization toolkit detecting biotinylated proteins with sub\u2010nanomolar sensitivity. In obese mice, we identified the piriform cortex (PIR) as a previously unrecognized extra\u2010hypothalamic sink for adipose\u2010derived leptin. This is associated with a localized neuroinflammatory signature, including significant induction of Il6. DuO\u2010SCOUT establishes a broadly applicable framework for dissecting the complex molecular logic of systemic organ\u2010organ communication.<\/jats:p>","DOI":"10.1002\/advs.77190","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:16:46Z","timestamp":1786699006000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual\u2010Organelle Secretome Conjugation and Organ\u2010Uptake Tracking (DuO\u2010SCOUT) Enables Deep and Sensitive Mapping of the Secreted Proteins"],"prefix":"10.1002","author":[{"given":"Fenglian","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences College of Biomedicine City University of Hong Kong  Hong Kong Hong Kong SAR China"},{"name":"Biotech and Health Centre Shenzhen Research Institute of City University of Hong Kong  Shenzhen Guangdong 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