Hypersound-Enhanced Intracellular Delivery of Drug-Loaded Mesoporous Silica Nanoparticles in a Non-Endosomal Pathway

The intracellular delivery efficiency of drug-loaded nanocarriers is often limited by biological barriers arising from the plasma membrane and the cell interior. In this work, the entering of doxorubicin (Dox)-loaded mesoporous silica nanoparticles (MSNs) into the cytoplasm was acoustically enhanced through direct penetration with the assistance of hypersound of gigahertz (GHz) frequency. Both fluorescence and cell viability measurements revealed that the therapeutic efficacy of Dox-loaded MSNs was significantly improved by tuning the power and duration of hypersound on demand with a nanoelectromechanical resonator. Mechanism studies with inhibitors illustrated that the membrane defects induced by the hypersound-triggered GHz acoustic streaming facilitated the Dox-loaded MSNs of 100-200 nm to directly penetrate through the cell membrane instead of via the traditional endocytosis, which highly increased the delivery efficiency by avoiding the formation of endosomes. This acoustic method enables the drug carriers to overcome biological barriers of the cell membrane and the endosomes without the limitation of carrier materials, which provides a versatile way of enhanced drug delivery for biomedical applications.