Targeted delivery of doxycycline with nanoparticles mitigates cytokine storm and reduces immune cell infiltration in LPS mediated lung inflammation.

Background: and Purpose: Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model. Experimental Approach: Cytokine storm and lung injury were induced using LPS and elastase in C57BL/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in BALF 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1, and MMPs were investigated in alveolar cells on day three after LPS administration. Key Results: Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-α, and IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit lung inflammasome pathways. Conclusion and Implications: IV administration of elastin antibody conjugated Doxycycline-loaded albumin Nps can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at a 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.