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Except for liver transplantation, no effective strategies are available for ALF therapy due to the rapid disease progression and narrow window of therapeutic time. Therefore, there is an urgent demand to explore the fast and effective modalities for ALF treatment. Herein, a multifunctional tetrahedral DNA nanoplatform (TDN) is constructed by incorporating tumor necrosis factor\u2010\u03b1 siRNA (siTNF\u2010\u03b1) through DNA hybridization and antioxidant manganese porphyrin (MnP4) via \u03c0\u2013\u03c0 stacking interaction with G\u2010quadruplex (G4) for surprisingly rapid and significant ALF therapy. TDN\u2010siTNF\u2010\u03b1\/\u2010G4\u2010MnP4 silences TNF\u2010\u03b1 of macrophages by siTNF\u2010\u03b1 and polarizes them to the anti\u2010inflammatory M2 phenotype, providing appropriate microenvironments for hepatocyte viability. Additionally, TDN\u2010siTNF\u2010\u03b1\/\u2010G4\u2010MnP4 scavenges intracellular ROS by MnP4, protecting hepatocytes from oxidative\u2010stress\u2010associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation by modulating the cell cycle. TDN\u2010siTNF\u2010\u03b1\/\u2010G4\u2010MnP4 shows almost complete liver accumulation after intravenous injection and exhibits excellent therapeutic efficacy of ALF within 2\u00a0h. The multifunctional DNA nanoformulation provides an effective strategy for rapid ALF therapy, expanding its application for innovative treatments of liver diseases.<\/jats:p>","DOI":"10.1002\/adma.202305826","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T12:04:41Z","timestamp":1696593881000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Multimodal Tetrahedral DNA Nanoplatform for Surprisingly Rapid and Significant Treatment of Acute Liver Failure"],"prefix":"10.1002","volume":"36","author":[{"given":"Hongyan","family":"Wei","sequence":"first","affiliation":[{"name":"Laboratory of Biomaterials and Translational Medicine Center for Nanomedicine The Third Affiliated Hospital Sun Yat\u2010sen University  600 Tianhe Road Guangzhou 510630 P. R. China"},{"name":"Guangdong Provincial Key Laboratory of Liver Disease  600 Tianhe Road Guangzhou 510630 P. R. China"},{"name":"Department of Obstetrics and Gynecology Chongqing Health Center for Women and Children  120 Longshan Road Chongqing 401147 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yi","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Translational Medicine Center for Nanomedicine The Third Affiliated Hospital Sun Yat\u2010sen University  600 Tianhe Road Guangzhou 510630 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenfang","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Translational Medicine Center for Nanomedicine The Third Affiliated Hospital Sun Yat\u2010sen University  600 Tianhe Road Guangzhou 510630 P. R. 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