Predesigned DNA Origami Nanodrills Mediate Controlled Pore Formation on a Plasma Membrane and Cell Death.

We presented an engineered DNA origami nanodrill that is capable of controlled attachment and penetration of the plasma membrane, thereby inducing cell damage and lytic death. The cap-and-stem-like DNA origami nanodrills were constructed, equipping them with addressable cholesterol tags on their caps for adherence to lipid bilayers. The subsequent insertion of the origami stems was initiated, enabling the generation of distinct transmembrane channels in various artificial and biological membranes. These nanodrills with plasma-membrane-disrupting functions resulted in mechanical damage to living cell membranes, leading to increased cytosolic calcium levels, enhanced intracellular protein release, and potent cytotoxicity against tumor cells. The further stimuli-responsive design enabled acid-triggered attachment of DNA nanodrills to the plasma membrane and subsequent cell damage in a pH-controlled fashion. This programmable origami nanodrill could serve as an artificial mediator of plasma-membrane rupture and cell death, thus potentially leading to the development of new therapeutic strategies to combat cancer.