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Epigallocatechin gallate (EGCG), a natural polyphenol with antioxidant and immunomodulatory activities, holds therapeutic potential for sepsis but is limited by rapid metabolism and low bioavailability. To overcome these limitations, we constructed ultrasmall Ce-EGCG nanoparticles (NPs) via one-pot metal-phenolic coordination self-assembly between cerium ions and EGCG. The resulting NPs exhibited excellent colloidal stability and efficient cellular internalization. Ce-EGCG NPs displayed dual catalase- and superoxide-dismutase-mimetic activities, scavenging both cytosolic and mitochondrial reactive oxygen species, and consistently outperformed equivalent doses of free EGCG and free Ce ions, demonstrating that the assembled metal-phenolic architecture is essential for the observed activity. In LPS- or H2O2-stimulated macrophages, Ce-EGCG NPs reversed Fe2+ overload, suppressed lipid peroxidation, and reprogrammed macrophages from a pro-inflammatory M1 toward an anti-inflammatory M2 phenotype. In CLP-induced septic mice, Ce-EGCG NPs ameliorated multi-organ injury, attenuated systemic cytokine storm, and improved survival, while showing favorable biosafety. Mechanistically, Ce-EGCG NPs activate the Nrf2\/HO-1\/NQO1 antioxidant axis and the GPX4\/SLC7A11\/ACSL4 anti-ferroptotic axis. Together, these findings show that Ce-EGCG NPs break the oxidative-ferroptotic-inflammatory cycle of sepsis through coordinated antioxidant, anti-ferroptotic, and immunomodulatory actions, offering a rationally designed nanotherapeutic strategy for sepsis and related inflammatory conditions.<\/jats:p>","DOI":"10.1021\/acsami.6c09916","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T20:48:46Z","timestamp":1787431726000},"page":"45936-45953","source":"Crossref","is-referenced-by-count":1,"title":["Ultrasmall Cerium-EGCG Nanoparticles Ameliorate Sepsis via Macrophage Reprogramming and Ferroptosis Inhibition"],"prefix":"10.1021","volume":"18","author":[{"given":"Weijie","family":"Wu","sequence":"first","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Xi","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghai","family":"Huang","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shushu","family":"Yang","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rao","family":"Fu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Shenzhen, China, 518106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Kang","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2951-5492","authenticated-orcid":true,"given":"Xinjin","family":"Chi","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"8","key":"2026101216071637700_cit1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"issue":"10219","key":"2026101216071637700_cit2","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"issue":"10219","key":"2026101216071637700_cit3","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/S0140-6736(19)33065-X","article-title":"A global accounting of sepsis","volume":"395","author":"Kempker","year":"2020","journal-title":"Lancet"},{"issue":"13","key":"2026101216071637700_cit4","doi-asserted-by":"publisher","first-page":"7396","DOI":"10.3390\/ijms25137396","article-title":"Navigating the Modern Landscape of Sepsis: Advances in Diagnosis and Treatment","volume":"25","author":"Jang","year":"2024","journal-title":"Int. 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