Harnessing self-assembled nanoplatform of Dexamethasone and α-linolenic acid for high-efficiency inhibition of pulmonary cytokine storm and fibrosis in mice

Cytokine storm and pulmonary fibrosis caused by Coronavirus Disease 2019 (COVID-19) are the two major culprits threatening human life and health. Herein, we engineered a novel disulfide-bridged carrier-free prodrug self-assembled nanoparticles (DSSL NPs) composed of Dexamethasone (Dex) and α-linolenic acid (LNA) for synergistic inhibition of cytokine storm and pulmonary fibrosis. DSSL NPs possess the capability to selectively target injured lung tissue and precisely release drugs after intravenous administration. Consequently, a single administration of DSSL NPs effectively mitigated pro-inflammatory cytokines and tissue damage in mice with lipopolysaccharide (LPS)-induced cytokine storm by blocking the TNF, NF-κB, and Toll-like receptor signaling pathways. Moreover, long-term administration of DSSL NPs alleviated the abnormal fibroblast activation and collagen deposition in mice with LPS-induced pulmonary fibrosis by inhibiting the Wnt-PCP signaling pathway without obvious Dex-related side effects. Together, DSSL NPs achieved the effect of ‘killing two birds with one stone’, presenting a safe and reliable strategy for comprehensive treatment for COVID-19-related diseases.