We set out to design, synthesize, and optimize a DNA-minimal cage capable of encapsulating oligonucleotide drugs to facilitate their delivery. Through rational design and optimization using in vitro assays, we have assembled the first DNA "nanosuitcase" that. can encapsulate a siRNA construct and release it upon recognition of an oligonucleotide trigger. The latter may be a mRNA or a microRNA (miRNA) which offers potential for dual or synergistic therapy. This construct assembles in near 100% yield, releases its cargo on demand, and can sustain biological conditions. Moreover, we find that the DNA scaffold is able to protect its cargo against site specific cleavage and nuclease degradation. Release of the cargo is performed with fixed cells using a FRET-enabled construct imaged by confocal microscopy and reveals that the DNA cage remains responsive at the molecular level in a complex cellular environment. We foresee this construct will be able to address challenges in drug delivery, more specifically in nontoxic delivery and targeted release.