Nucleic acid nanocapsules (NANs) are DNA-functionalized micelles designed for the triggered release of therapeutic nucleic acids into cells. As nanocarriers, NANs have demonstrated attractive properties such as resistance to enzymatic degradation of nucleic acid cargo, receptor-mediated cellular uptake, and the tunable delivery of bioactive DNA-surfactant conjugates. Here we dissect the cytosolic delivery of therapeutic DNA-surfactant conjugates mediated by the NAN platform. So far, we have shown the stability of such particles in serum and have identified key pathways involved in the cellular uptake of NANs using pharmacological inhibitors. Using mass spectrometry and surface enhanced Raman spectroscopy, we present evidence that the triggered degradation of NANs produces DNA-surfactant conjugates capable of passively traversing a lipid membrane, which is central to their cytosolic delivery and therapeutic function. Finally, we found that introducing a minor structural change in the NAN’s components could produce a measurable change in its <i>in vitro </i>activity, demonstrating the potential to carry out structure-activity studies to understand the design and improve the function of NANs.

Modular DNA micelles for the controlled delivery of therapeutic DNA-surfactant conjugates

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