A CD54-targeted magneto-responsive nanotheranostic for precision treatment of viral pneumonia via CTSB-mediated PANoptosis inhibition

Broad-spectrum therapeutics that simultaneously halt viral replication and mitigate cytokine storms are urgently needed for respiratory viral pandemics. In this study, a magneto-active nanotheranostic platform (IO@CA/P) was developed by conjugating the Cathepsin B (CTSB) inhibitor CA-074 and a CD54-targeting cyclic peptide to superparamagnetic iron oxide nanoparticles. IO@CA/P exhibited broad-spectrum antiviral activity against SARS-CoV-2 (Omicron, Delta), influenza (H1N1, H3N2), and respiratory syncytial virus by blocking viral entry. CD54 targeting combined with magnetic navigation achieved a 16.3-fold increase in pulmonary drug accumulation compared to free CA-074. The SPIO core acted as an antioxidant nanozyme to scavenge reactive oxygen species, synergizing with CA-074 to stabilize lysosomal membranes and block CTSB-mediated PANoptosis. Non-invasive MRI established a quantitative correlation between T1-signal intensity and pneumonia severity, enabling real-time monitoring of drug biodistribution. In murine models of IAV and SARS-CoV-2 infection, IO@CA/P significantly reduced viral loads and pulmonary inflammation via the CTSB-PANoptosis axis. Furthermore, IO@CA/P independently attenuated LPS-induced sterile inflammation and subsequent fibrotic/thrombotic sequelae, highlighting its broader anti-inflammatory applicability beyond direct antiviral mechanisms. Therefore, this host-directed nanotheranostic strategy has potential for clinical translation to combat emerging respiratory viruses and mitigating life-threatening immunopathology.