Mechanical stretching of cells and lipid nanoparticles for nucleic acid delivery

Gene therapy has gained popularity in the treatment of incurable diseases. However, cell components, such as surface membrane, cytoskeleton protein, and nuclear envelope, retard the transport of nucleic acids, lowering the transfection efficiency. We developed a physical-chemical hybrid platform (S-RCLs) involving cationic lipid nanoparticles (RCLs) exposed to cyclic stretch. The transfection efficiency and delivery mechanisms of S-RCLs for siRNAs and pDNAs (plasmid DNAs encoding luciferase) were investigated. S-RCLs effectively delivered both siRNAs and pDNAs by overcoming the cell barriers. Mechanistically, S-RCLs promote the cellular uptake mediated by CD44, EH-domain containing 2 (EHD2), and caveolin-1 (CAV-1); intracellular transport via MAP6 Domain Containing 1 (Map6d1) and F-actin; and DNA transcription regulated by LSM3 and Hist1h3e in the nucleus. Thus, S-RCLs are a promising hybrid platform with excellent efficiency and biocompatibility for gene delivery both in vitro and in vivo.