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, reactive oxygen species (ROS) level elevation, 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 therapeutic time window. Therefore, there is an urgent demand to explore fast and effective modalities for ALF treatment. Herein, a multifunctional tetrahedral DNA nanoplatform (TDN) is constructed by incorporating the 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 and TDN, protecting hepatocytes from oxidative stress‐associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation via 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 for liver diseases.This article is protected by copyright. All rights reserved

Emerging nanoparticle platforms for CpG oligonucleotide delivery

“…DNA tetrahedra, which are easily self-assembled from four or six oligonucleotides, show promising efficacy in immobilizing nucleic acids in defined orientations and spacing on the DNA tetrahedra surfaces. 59,[72][73][74][75] DNA tetrahedra were effective in increasing the potency of CpG motifs to enter into the macrophages and induce cytokines from macrophages. Fan and collaborators appended unmethylated CpG motifs to the multivalent DNA tetrahedra.…”

Advances in Noninvasive Molecular Imaging Probes for Liver Fibrosis Diagnosis

“…The M1/M2 phenotype of these macrophages determines their pro-inflammatory or anti-inflammatory effects, thereby influencing the progression of fibrosis in the later stages [ 113 ]. For example, Wei and colleagues [ 114 – 117 ] developed a multifunctional tetrahedral DNA nanoplatform (TDN-siTNF-α/-G4-MnP4), which can silence the expression of TNF-α in macrophages using TNF-α siRNA and polarize macrophages into the anti-inflammatory M2 phenotype. Importantly, this platform can eliminate intracellular ROS and promote hepatocyte proliferation, providing a synergistic and effective therapeutic strategy for acute liver failure.…”