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.