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.

Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3′ end of RNA polymerase Ⅱ transcripts from over 60% of human genes. APA is derived from the existence of multiple polyadenylation signals (PAS) within the same transcript, and results in the differential inclusion of sequence information at the 3′ end. While APA can occur between two PASs allowing for generation of transcripts with distinct coding potential from a single gene, most APA occurs within the untranslated region (3′UTR) and changes the length and content of these non-coding sequences. APA within the 3′UTR can have tremendous impact on its regulatory potential of the mRNA through a variety of mechanisms, and indeed this layer of gene expression regulation has profound impact on processes vital to cell growth and development. Recent studies have particularly highlighted the importance of APA dysregulation in cancer onset and progression. Here, we review the current knowledge of APA and its impacts on mRNA stability, translation, localization and protein localization. We also discuss the implications of APA dysregulation in cancer research and therapy.