NQO1-Activatable Circular Antisense Oligonucleotides for Tumor-Cell-Specific Survivin Gene Silencing and Antitumor Therapy

NAD(P)H:quinone oxidoreductase-1 (NQO1), a protein highly expressed in tumor cells, serves as an excellent trigger for releasing drugs specifically within tumor cells. In this study, we designed an activatable circular antisense oligonucleotide (cASO) by incorporating a head-to-tail cyclization mediated by an NQO1-responsive trimethyl-locked quinone propionate (Q3PA), coupled with a self-immolative linker. The resulting circular structure prevented the cASO from binding to the target mRNA, thereby avoiding gene silencing. However, upon encountering NQO1, the circular form was converted to a linear form, leading to the silencing of the targeted gene. In vitro experiments demonstrated significant tumor-cell-specific activity of the cASO, while in vivo studies using an A549-Luc orthotopic lung tumor model revealed a substantial antitumor effect, primarily attributed to the suppression of survivin expression. This NQO1-activatable cASO represents a novel strategy for achieving tumor-cell-specific gene silencing and holds promise for the development of ASO prodrugs with enhanced therapeutic potentials.