A Cyanine-Mediated Self-Assembly System for the Construction of a Two-in-One Nanodrug.

The combination of gene therapy and chemotherapy provides a promising avenue to treat and eradicate cancer. However, the significantly different physicochemical properties of nucleic acids and drug molecules hinder the potential direct integration of these two agents into a single particle, limiting the construction of an ideal delivery system to achieve synergistic antitumor effectiveness. Herein, we developed a simple and versatile approach to prepare a series of two-in-one nanodrugs through direct self-assembly of cyanine-labeled single-stranded DNA (Cys-DNA) and different types of drug molecules. Molecular dynamics simulation showed that the Cys introduced into the DNA could enhance the noncovalent interaction between Cys-DNA and drug molecules. Therefore, more drug molecules were incorporated into Cys-DNA, tending to spontaneously form hybrid Cys-DNA/drug nanosphere. Such nanospheres serve as both carriers and cargoes, excluding the extra use of nontherapeutic excipients and showing ultrahigh drug loading capacity. Following this approach, an antisense oligonucleotides/doxorubicin nanodrug model was constructed, demonstrating the significant synergistic anti-tumor therapeutic effect. As a proof of the concept, our study establishes a simple and reproducible two-in-one nucleic acid-based drug formulation, facilitating future development of drug-delivery systems.