Reconfigurable Amphiphilic DNA Nanotweezer for Targeted Delivery of Therapeutic Oligonucleotides

Abstract

Amphiphilic lipid oligonucleotide conjugates are powerful molecular-engineering materials that have been used for delivery of therapeutic oligonucleotides. However, conventional lipid oligonucleotide conjugates suffer from poor selectivity to target cells due to the nonspecific interaction between lipid tails and cell membranes. Herein, a reconfigurable DNA nanotweezer consisting of a c-Met aptamer and bischolesterol-modified antisense oligonucleotide was designed for c-Met-targeted delivery of therapeutic antisense oligonucleotides. The c-Met aptamer is used to keep the DNA nanotweezer in a “closed” state, which enables the hydrophobic interaction within bischolesterol moieties. As a result, the amphiphilic DNA nanotweezer shows only a weak interaction with the cell membrane. Upon the release of the c-Met aptamer, the DNA nanotweezer converts to an “open” state, which facilitates the insertion of a cholesterol moiety into the cell membrane. Thus, the reconfigurable DNA nanotweezer enables the selective membrane anchoring of the DNA nanotweezer in cancerous cells that highly expressed c-Met protein. Moreover, this amphiphilic DNA nanotweezer shows enhanced accumulation at the tumor site and the inhibition of tumor growth. Taking advantage of the stimuli-responsive membrane anchoring capability, this reconfigurable DNA nanotweezer could be further explored as a smart multifunctional platform for cancer therapy.

c-Met protein-induced conformational transition of the amphiphilic DNA nanotweezer from “closed” to “open” state enables the tunable membrane anchoring capability for enhanced targeted delivery.