A Susceptible Cell‐Selective Delivery (SCSD) of mRNA‐Encoded Cas13d Against Influenza Infection

To bolster the capacity for managing potential infectious diseases in the future, it is critical to develop specific antiviral drugs that can be rapidly designed and delivered precisely. Herein, a CRISPR/Cas13d system for broad-spectrum targeting of influenza A virus (IAV) from human, avian, and swine sources is designed, incorporating Cas13d mRNA and a tandem CRISPR RNA (crRNA) specific for the highly conserved regions of viral polymerase acidic (PA), nucleoprotein (NP), and matrix (M) gene segments, respectively. Given that the virus targets cells with specific receptors but is not limited to a single organ, a Susceptible Cell Selective Delivery (SCSD) system is developed by modifying a lipid nanoparticle with a peptide mimicking the function of the hemagglutinin of influenza virus to target sialic acid receptors. The SCSD system can precisely deliver an all-RNA-based CRISPR/Cas13d system into potentially infected cells. This drug is shown to reduce the viral load in the lungs by 2.37 log₁₀ TCID₅₀ mL^-1 and protect 100% of mice from lethal influenza infection. The SCSD-based CRISPR/Cas13d system shows promise for the flexible and efficient therapy of infections caused by rapidly evolving and novel viruses.