Reconfigurable\nAmphiphilic DNA Nanotweezer for Targeted\nDelivery of Therapeutic Oligonucleotides

Amphiphilic lipid oligonucleotide conjugates are powerful\nmolecular-engineering\nmaterials that have been used for delivery of therapeutic oligonucleotides.\nHowever, conventional lipid oligonucleotide conjugates suffer from\npoor selectivity to target cells due to the nonspecific interaction\nbetween lipid tails and cell membranes. Herein, a reconfigurable DNA\nnanotweezer consisting of a c-Met aptamer and bischolesterol-modified\nantisense oligonucleotide was designed for c-Met-targeted delivery\nof therapeutic antisense oligonucleotides. The c-Met aptamer is used\nto keep the DNA nanotweezer in a “closed” state, which\nenables the hydrophobic interaction within bischolesterol moieties.\nAs a result, the amphiphilic DNA nanotweezer shows only a weak interaction\nwith the cell membrane. Upon the release of the c-Met aptamer, the\nDNA nanotweezer converts to an “open” state, which facilitates\nthe insertion of a cholesterol moiety into the cell membrane. Thus,\nthe reconfigurable DNA nanotweezer enables the selective membrane\nanchoring of the DNA nanotweezer in cancerous cells that highly expressed\nc-Met protein. Moreover, this amphiphilic DNA nanotweezer shows enhanced\naccumulation at the tumor site and the inhibition of tumor growth.\nTaking advantage of the stimuli-responsive membrane anchoring capability,\nthis reconfigurable DNA nanotweezer could be further explored as a\nsmart multifunctional platform for cancer therapy.