Coiled-coil lipopeptides mediated membrane fusion based drug delivery into a mimicking lung organ

Abstract

The complementary fusogenic coiled-coil lipopeptides CPE and CPK have gained attention as mediators of drug delivery via membrane fusion for various therapeutic applications. However, the models used in these studies were mainly 2D cell cultures and animal models, leaving the in-site interaction and physiological effects of this lipopeptide system in vivo unclear. To address this, we constructed two 3D cell models in vitro, a mimicking lung organ (mLO) using 3D printed hydrogel cell scaffold and alveolar organoids (AOs) derived from mouse adult stem cells. These models were used to evaluate the lipopeptide modified membrane fused drug delivery system (MF-DDS) and showed the details of drug delivery in treating the acute lung injury (ALI) model based on the 3D models. Our results revealed that MF-DDS demonstrated superior drug delivery efficiency in mLO, particularly when cultured dynamically on a chip compared to a static U-shaped plate. Importantly, the MF-DDS demonstrated great biocompatibility with no significant changes in macrophage phenotype, inflammatory cytokine secretion, and lung barrier integrity on the mLO after the cell membrane fused with the artificial lipid membrane. In the lipopolysaccharide (LPS) induced injury model using mLO, the MF-DDS delivered naringin effectively, significantly reduced inflammatory factor secretion, macrophage polarization, and protected lung barrier disruption. Furthermore, the safety and effectiveness of MF-DDS were validated using AOs, underscoring its potential in treating ALI. These findings offer critical insights into the interactions between MF-DDS and organ systems, paving the way for faster and more precise evaluations of drug delivery strategies for disease treatment.