Photolabile Self-Immolative DNA-Drug Nanostructures

It is often desirable to simultaneously target different cellular pathways to improve the overall efficacy of a drug or to circumvent drug resistance in therapeutic treatments. Nucleic acid therapy has been considered attractive for such combination therapies due to its possible synergistic effects with traditional chemotherapy, especially for targets that do not yet have small molecule inhibitors. However, the co-delivery of nucleic acids and chemotherapeutics typically involves the use of inherently cytotoxic/immunogenic, polycationic carrier systems, for which the benefit is often overshadowed by adverse side effects. Herein, we detail the construction and characterization of a DNA-drug nanostructure that consists almost entirely of payload molecules. Upon triggering with light, the nanostructure collapses via an irreversible, self-immolative process and releases free oligonucleotides, drug molecules, and small molecule fragments. We demonstrate that the nanostructures can be used as a dual-delivery agent in vitro without a carrier system and that the released model drug (camptothecin, CPT) exhibits similar levels of cytotoxicity as unmodified drugs toward cancer cells.