Noncovalent and precise loading of small molecule drugs on DNA nanocarriers

DNA nanocarriers have been utilized for delivering a variety of functional cargo molecules, demonstrating unique properties such as designable and programmable structures, site-specific functionality, and superior biocompatibility. However, nucleic acid nanocarriers present significant limitations when it comes to loading small molecule drugs. Covalent integration of small molecule drugs into nucleic acid nanocarriers usually requires complex organic chemical reactions. Here we report a new method that enables the noncovalent and precise loading of small molecule drugs onto DNA nanocarriers. This is achieved through the formation of small molecule-mediated non-canonical base pairing. As a proof of principle, we successfully loaded cordycepin into aptamer-functionalized DNA nanoparticles and achieved a significant therapeutic effect in melanoma-bearing mice. This approach expands the range of small molecule drugs that can be loaded onto DNA nanostructures, particularly benefiting the synergistic therapy that combines small molecule drugs with nucleic acid drugs.