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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Rutin is a flavonoid glycoside with well-documented antioxidant and anti-inflammatory activities in preclinical models, but its oral bioavailability is poor due to extensive presystemic metabolism. Following oral administration, intact rutin reaches the colon largely unabsorbed, where gut microbiota convert it to quercetin aglycone, which is further metabolized to circulating conjugated metabolites and local phenolic acid derivatives. Accumulating evidence, derived predominantly from preclinical studies, suggests this metabolic activation can be usefully conceptualized as a microbiota-activated prodrug system. This challenges conventional formulation strategies that only increase parent compound exposure. In this review, we propose a metabolism-oriented conceptual framework for oral rutin delivery design. We compare nano-delivery systems and structural modifications strategies across pharmacokinetics, metabolic regulation, safety, manufacturability, and translational feasibility. Nano-delivery systems are functionally reclassified into four absorption, distribution, metabolism, excretion (ADME) -oriented categories based on their primary pharmacokinetic objectives. While numerous preclinical studies report improved bioavailability and efficacy, human metabolite-resolved pharmacokinetic data remain extremely limited, and no European Food Safety Authority (EFSA) -authorized health claims exist for rutin. This review provides a new conceptual framework for selecting oral rutin delivery strategies based on metabolic objectives rather than solely on improving solubility or systemic exposure.<\/jats:p>","DOI":"10.3390\/ijms27156543","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:11:42Z","timestamp":1784787102000},"page":"6543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Metabolism-Guided Framework for Selecting Structural Modification or Nano-Delivery Strategies for Oral Rutin"],"prefix":"10.3390","volume":"27","author":[{"given":"Ting","family":"He","sequence":"first","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei-Sheng","family":"Fan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Jia","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding-Qiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-057X","authenticated-orcid":false,"given":"Yu-Ping","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liang, T.-Z., Lin, Y.-X., Jia, S.-H., Jiao, J.-Y., Zhang, Z.-X., Zhu, Z., Liu, Y.-J., Xu, B., and Lei, H.-M. 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