Multimodal Tetrahedral DNA Nanoplatform for Surprisingly Rapid and Significant Treatment of Acute Liver Failure

Abstract Acute liver failure (ALF) is a life‐threatening disease associated with the rapid development of inflammatory storms, level elevation of reactive oxygen species (ROS), and hepatocyte necrosis, which results in high short‐term mortality. 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‐α siRNA (siTNF‐α) through DNA hybridization and antioxidant manganese porphyrin (MnP4) via π–π stacking interaction with G‐quadruplex (G4) for surprisingly rapid and significant ALF therapy. TDN‐siTNF‐α/‐G4‐MnP4 silences TNF‐α of macrophages by siTNF‐α and polarizes them to the anti‐inflammatory M2 phenotype, providing appropriate microenvironments for hepatocyte viability. Additionally, TDN‐siTNF‐α/‐G4‐MnP4 scavenges intracellular ROS by MnP4, protecting hepatocytes from oxidative‐stress‐associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation by modulating the cell cycle. TDN‐siTNF‐α/‐G4‐MnP4 shows almost complete liver accumulation after intravenous injection and exhibits excellent therapeutic efficacy of ALF within 2 h. The multifunctional DNA nanoformulation provides an effective strategy for rapid ALF therapy, expanding its application for innovative treatments of liver diseases.