Single-dose cathepsin L CRISPR nanotherapy mitigates PASC-like lung damage in hamsters

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.