RNAi therapy targeting coronavirus genomes, pulmonary delivery strategies and design principles: A review.

With the persistent global outbreak of Coronavirus Disease 2019 (COVID-19), the development of effective antiviral strategies has become a top priority in public health. RNA interference (RNAi), an effective gene-silencing technique, presents a novel therapeutic approach to combat coronavirus replication. RNA interference (RNAi) is a potent gene-silencing approach that offers a therapeutic route to suppress coronavirus replication. Clinical translation of small interfering RNA (siRNA), however, faces substantial obstacles, notably cross-strain universality, off-target effects, and targeted delivery. This review summarizes recent advances in RNAi-mediated inhibition of coronaviruses at the genomic level, emphasizing RNAi applications to impede SARS-CoV-2 replication and transmission. By evaluating RNAi strategies aimed at specific viral components-RNA-dependent RNA polymerase (RdRp), spike protein (S), envelope protein (E), membrane protein (M), nucleocapsid protein (N), and other essential genes-we illustrate the distinct specificity and efficacy of RNAi across binding sites and identify candidate universal targets for human-transmitted coronaviruses. We also assess the strengths and limitations of delivery platforms, including liposomes, polymers, nanoparticles, and viral vectors. Finally, we highlight inhalation-based and other targeted delivery approaches as promising routes for siRNA therapeutics against COVID-19 and other pulmonary diseases. Advances in gene editing and nanotechnology continue to broaden the prospects for effective siRNA delivery.