Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly intersp...Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly interspaced short palindromic repeats(CRISPR)–CasRx nanotherapy targeting the host enzyme cathepsin L(SCNC)effectively reduces acute SARS-CoV-2 infection in Syrian hamsters,with antiviral efficacy comparable to Paxlovid.Importantly,SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection,a recognized PASC time point.Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways.Thus,SCNC exerts a dual mechanism:host-directed viral inhibition and promotion of epithelial repair with reduced inflammation.This distinguishes it from therapies focused solely on viral suppression or symptom relief.These findings support SCNC as a promising therapeutic candidate for acute infection and,particularly,for PASC-related lung injury,where options remain limited.展开更多
文摘Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly interspaced short palindromic repeats(CRISPR)–CasRx nanotherapy targeting the host enzyme cathepsin L(SCNC)effectively reduces acute SARS-CoV-2 infection in Syrian hamsters,with antiviral efficacy comparable to Paxlovid.Importantly,SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection,a recognized PASC time point.Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways.Thus,SCNC exerts a dual mechanism:host-directed viral inhibition and promotion of epithelial repair with reduced inflammation.This distinguishes it from therapies focused solely on viral suppression or symptom relief.These findings support SCNC as a promising therapeutic candidate for acute infection and,particularly,for PASC-related lung injury,where options remain limited.
