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While aqueous humor (AH) proteomics holds promise for uncovering disease mechanisms and biomarkers, its proteome coverage has been constrained by limited sample volume and low protein concentration. Here, we present quaternary lanthanide\u2010based macroporous metal\u2013organic frameworks to enrich AH proteins and a corresponding streamline for ultrasensitive trace aqueous humor proteome (TAHP). TAHP permits end\u2010to\u2010end sample\u2010to\u2010result analysis in &lt;4 h and quantifies &gt;3300 proteins from merely just 1\u00a0\u00b5L AH. Applied to cataract (\n                    <jats:italic>n<\/jats:italic>\n                    = 31) and DME (\n                    <jats:italic>n<\/jats:italic>\n                    = 52) clinical cohorts, TAHP delineated DME molecular landscape and uncovered proteomic signatures of pathological angiogenesis, amplified inflammatory signaling, and compromised antioxidant defenses. By integrating machine learning, we prioritized PAFAH2 as a high\u2010performance single biomarker for DME stratification (AUC = 0.98 \u00b1 0.02). TAHP enables rapid, robust and deep AH proteomics, offering a broadly accessible platform to decipher proteome atlas across fundus diseases not limited to DME.\n                  <\/jats:p>","DOI":"10.1002\/adma.74577","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:12:29Z","timestamp":1786428749000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trace Aqueous Humor Proteome via Macroporous MOF Platform Reveals High\u2010Resolution Molecular Phenotypes of Diabetic Macular Edema"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3057-8097","authenticated-orcid":false,"given":"Shuang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Surgical Intensive Care Unit School of Medicine and School of Biomedical Engineering Xinhua Hospital Shanghai Jiao Tong University  Shanghai People's Republic of 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Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2948-8570","authenticated-orcid":false,"given":"Yujie","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Surgical Intensive Care Unit School of Medicine and School of Biomedical Engineering Xinhua Hospital Shanghai Jiao Tong University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiting","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Institute for Personalized Medicine Shanghai Jiao Tong University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6642-7451","authenticated-orcid":false,"given":"Renbing","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of China"},{"name":"State Key Laboratory of Eye Health, Department of Ophthalmology, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9135-0940","authenticated-orcid":false,"given":"Peiwei","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of China"},{"name":"State Key Laboratory of Eye Health, Department of Ophthalmology, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1549-3499","authenticated-orcid":false,"given":"Xianting","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Surgical Intensive Care Unit School of Medicine and School of Biomedical Engineering Xinhua Hospital Shanghai Jiao Tong University  Shanghai People's Republic of China"},{"name":"State Key Laboratory of Oncogenes and Related Genes Institute for Personalized Medicine Shanghai Jiao Tong University  Shanghai People's Republic of 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