The therapeutic potential of RNA and DNA is evident from numerous formulations approved by the FDA in recent years, with formulations based on RNAi standing out as a successful example. The new class of medicines based on RNAi combines the process of diagnosis and treatment via sequence-specific recognition of biomarker mRNAs and downregulation of their translation. While this approach proved clinically successful, safer, and more personalized options that mitigate adverse effects can be revealed by separating diagnostic and treatment steps. A concept is introduced that allows RNAi therapies to selectively exert their function within diseased cells. The reconfigurable nucleic acid nanoparticles, or recNANPs, recognize overexpressed cancer biomarkers and conditionally release RNAi inducers targeting apoptosis inhibitors in pancreatic cancer cells. RecNANPs are non-immunostimulatory, achieve prolonged gene silencing compared to conventional RNAi inducers, and can be combined with chemotherapy. It is anticipated that this modular platform will enable further advancements in the development of biocompatible nanodevices activated by intracellular variables of choice, facilitating treatment with a repertoire of nucleic acid therapies.