Receptor-Free Cellular Internalization of DNA Micelles Driven by Membrane Interaction

Cellular uptake of nanoparticles is essential for significant therapeutic effects at the target site in drug-delivery applications. Various endocytosis pathways have been reported; however, the internalization of nanoparticles depends on their physical and chemical properties. We previously developed nucleic acid-based micelles (DNA micelles) as a drug-delivery system and observed that the presence of lipid moieties in amphiphilic lipid-modified DNAs plays a crucial role in cellular uptake. In this study, we investigate the cellular internalization of DNA micelles and evaluate the role of membrane interactions in this process. Our results suggest that the internalization of DNA micelles is primarily driven by direct interaction with the cell membrane rather than binding to receptors on the cell membrane. Using both artificial membrane models and live cells, we observed that DNA micelles are inserted into the membrane and internalized through the formation of intracellular vesicles. Comparative studies with pristine DNA further revealed that lipid-modified nucleic acids are critical for the cellular uptake of DNA micelles. Overall, these findings provide insight into receptor-independent internalization in which nanoparticles enter cells through direct interactions with the membrane.