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.

Activated fibroblasts are major mediators of pulmonary fibrosis. Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix (ECM) in the lung interstitial section. Therefore, fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis (IPF). Here, we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1 (LPA₁) and the inflammatory pathway through tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) in fibroblasts. First, we synthesized a series of LPA₁ antagonists, AM095 and AM966, derived amino lipids (LA lipids) which were formulated into LA-lipid nanoparticles (LA-LNPs) encapsulating mRNA. Specifically, LA5-LNPs, with AM966 head group and biodegradable acetal lipid tails, showed efficient A20 mRNA delivery to lung fibroblasts in vitro (80.2% ± 1.5%) and ex vivo (17.2% ± 0.4%). When treated to primary mouse lung fibroblasts (MLF), this formulation inhibited fibroblast migration and collagen production, thereby slowing the progression of IPF. Overall, LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.