Lung-selective 25-hydroxycholesterol nanotherapeutics as a suppressor of COVID-19-associated cytokine storm

Area of Science:

• Nanomedicine
• Virology
• Immunology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, often leading to severe pneumonia and acute respiratory distress syndrome (ARDS).
• COVID-19 pathogenesis involves decreased 25-hydroxycholesterol (25-HC) and elevated cytokine levels, driven by NF-κB and SREBP2 signaling pathways.
• Targeted drug delivery to the lungs is a critical strategy for managing COVID-19 due to SARS-CoV-2's primary site of infection.

Purpose of the Study:

• To develop and evaluate a novel therapeutic agent for severe COVID-19.
• To investigate the potential of 25-hydroxycholesterol and didodecyldimethylammonium bromide nanovesicles (25-HC@DDAB) as a treatment.
• To assess the efficacy of 25-HC@DDAB in restoring cholesterol levels and suppressing the cytokine storm in COVID-19 patients.

Main Methods:

• Development of 25-HC@DDAB nanovesicles for selective lung accumulation.
• Evaluation of 25-HC@DDAB's effect on NF-κB and SREBP2 signaling pathways in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients.
• Measurement of inflammatory cytokine levels following 25-HC@DDAB treatment.

Main Results:

• 25-HC@DDAB nanovesicles demonstrated selective accumulation in lung tissues.
• The treatment effectively downregulated NF-κB and SREBP2 signaling pathways in COVID-19 patient-derived PBMCs.
• Significant reduction in inflammatory cytokine levels was observed, mitigating the cytokine storm.

Conclusions:

• 25-HC@DDAB represents a promising therapeutic candidate for severe COVID-19.
• This nanovesicle formulation effectively addresses key pathological mechanisms, including cholesterol imbalance and hyperinflammation.
• The findings support the potential of 25-HC@DDAB for treating symptoms like decreased cholesterol and cytokine storm in severe SARS-CoV-2 infections.