Peptidic defective interfering gene nanoparticles against Omicron, Delta SARS-CoV-2 variants and influenza A virus in vivo

• Published in: Signal transduction and targeted therapy 2022-08, Vol.7 (1), p.266-10, Article 266
• Main Authors: Zhao, Hanjun, Zhang, Chuyuan, Lam, Hoiyan, Meng, Xinjie, Peng, Zheng, Yeung, Man Lung, Chan, Jasper Fuk-Woo, Kai-Wang To, Kelvin, Yuen, Kwok-Yung
• Format: Article
• Language: English
• Subjects: 631/154/152; 631/326; Animals; Cancer Research; Cell Biology; COVID-19 - genetics; Cricetinae; Drug delivery; Gene expression; Gene therapy; Gene transfer; Genomes; Humans; Influenza; Influenza A; Influenza A virus; Influenza A Virus, H1N1 Subtype - genetics; Influenza, Human - prevention & control; Internal Medicine; Lungs; Medicine; Medicine & Public Health; Mice; Nanoparticles; Oncology; Pathology; Peptides; Peptides - genetics; Peptides - pharmacology; Replication; Respiratory tract; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Viruses
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-022-01138-0

Defective interfering genes (DIGs) are short viral genomes and interfere with wild-type viral replication. Here, we demonstrate that the new designed SARS-CoV-2 DIG (CD3600) can significantly inhibit the replication of SARS-CoV-2 including Alpha, Delta, Kappa and Omicron variants in human HK-2 cells and influenza DIG (PAD4) can significantly inhibit influenza virus replication in human A549 cells. One dose of influenza DIGs prophylactically protects 90% mice from lethal challenge of A(H1N1)pdm09 virus and CD3600 inhibits SARS-CoV-2 replication in hamster lungs when DIGs are administrated to lungs one day before viral challenge. To further investigate the gene delivery vector in the respiratory tract, a peptidic TAT2-P1&LAH4, which can package genes to form small spherical nanoparticles with high endosomal escape ability, is demonstrated to dramatically increase gene expression in the lung airway. TAT2-P1&LAH4, with the dual-functional TAT2-P1 (gene-delivery and antiviral), can deliver CD3600 to significantly inhibit the replication of Delta and Omicron SARS-CoV-2 in hamster lungs. This peptide-based nanoparticle system can effectively transfect genes in lungs and deliver DIGs to inhibit SARS-CoV-2 variants and influenza virus in vivo, which provides the new insight into the drug delivery system for gene therapy against respiratory viruses.