Herpesvirus‐Mimicking DNAzyme‐Loaded Nanoparticles as a Mitochondrial DNA Stress Inducer to Activate Innate Immunity for Tumor Therapy

Abstract

Virus‐based immunotherapy is a promising approach to treat tumor. Closely mimicking the structure and sequential infection processes of natural viruses is highly desirable for effective tumor immunotherapy but remains challenging. Here, inspired by the robust innate immunity induced by herpesvirus, a herpesvirus‐mimicking nanoparticle (named Vir‐ZM@TD) is engineered for tumor therapy by mimicking the structure and infection processes of herpesvirus. In this biomimetic system, DNAzyme‐loaded manganese‑doped zeolitic imidazolate framework‑90 (ZIF‐90) nanoparticles (ZM@TD) mimic the virus nucleocapsid containing the genome; the erythrocyte membrane mimics the viral envelope; and two functional peptides, RGD and HA2 peptides, resemble the surface glycoprotein spikes of herpesvirus. Vir‐ZM@TD can both effectively evade rapid clearance in the blood circulation and closely mimic the serial infection processes of herpesvirus, including specific tumor targeting, membrane fusion‐mediated endosomal escape, and TFAM (transcription factor A, mitochondrial) deficiency‐triggered mitochondrial DNA stress, as well as the release of manganese ions (Mn2+) from organelles into the cytosol, ultimately effectively priming cGAS‐STING pathway‐mediated innate immunity with 68% complete regression of primary tumors and extending by 32 days the median survival time of 4T1‐tumor‐bearing mice.

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

“…Mn 2+ has been proved to show cGAS-STING activation activities as a novel cGAS agonist ( 81 ). Although Mn 2+ based nanomaterials can be directly used to activate cGAS-STING signaling, their biomedical uses are dramatically restricted by their low stability and biocompatibility.…”

“…cGAS-STING can regulate tumorigenesis, participate in autoimmunity and is also essential for the host defense against different kinds of pathogens ( 81 ). Thus, the active regulation of cGAS-STING signaling events is expected to develop novel therapeutics against tumor and infections.…”

MnOOH-Catalyzed Autoxidation of Glutathione for Reactive Oxygen Species Production and Nanocatalytic Tumor Innate Immunotherapy

“…Ingeniously and simultaneously, MnOOH displayed catalase-like activity to decompose H 2 O 2 for O 2 supplement in the GSH autoxidation. Subsequently, tumor-derived DNA fragments produced by catalytic therapy activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, which could be sensitized by the generated abundant Mn 2+ . − Moreover, Mn 2+ was found to be an effective cGAS engine, directly activating cGAS independent of cytosolic DNA and triggering a noncanonical catalytic synthesis of 2′3′- cyclic GMP-AMP (cGAMP). − …”

An Integrated Polymeric mRNA Vaccine without Inflammation Side Effects for Cellular Immunity Mediated Cancer Therapy

“…Therapeutic mRNA cancer vaccines aim to elicit long-term antitumor immunity by vaccinating patients with mRNA encoding cancer-specific antigens and immunostimulant adjuvants. [22][23][24][25][26] However, naked mRNA is an intrinsically unstable and negatively charged hydrophilic macromolecule, facing various physical (e.g., electrostatic repulsion due to cell membranes) and biochemical barriers (e.g., extracellular RNase degradation) during the intracellular entry process. [27] Thus, efficient mRNA delivery into cytoplasm is a key factor to achieving satisfactory therapeutic effects for mRNA-based vaccination.…”