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Herein, a CRISPR\/Cas13d system for broad\u2010spectrum 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\u2010RNA\u2010based CRISPR\/Cas13d system into potentially infected cells. This drug is shown to reduce the viral load in the lungs by 2.37 log<jats:sub>10<\/jats:sub> TCID<jats:sub>50<\/jats:sub>\u00a0mL<jats:sup>\u22121<\/jats:sup> and protect 100% of mice from lethal influenza infection. The SCSD\u2010based CRISPR\/Cas13d system shows promise for the flexible and efficient therapy of infections caused by rapidly evolving and novel viruses.<\/jats:p>","DOI":"10.1002\/advs.202414651","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T14:51:42Z","timestamp":1736520702000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Susceptible Cell\u2010Selective Delivery (SCSD) of mRNA\u2010Encoded Cas13d Against Influenza Infection"],"prefix":"10.1002","volume":"12","author":[{"given":"Zhuanli","family":"Wu","sequence":"first","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety College of Veterinary Medicine China Agricultural University  Beijing 100193 China"},{"name":"Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry 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