RNAi-based therapeutics have shown biomedical potential; however, safe and efficient delivery of RNA remains a barrier for clinical applications. Nucleic acid-based nanoparticles (NANPs) programmed to self-assemble into structures with multiple therapeutic nucleic acids (TNAs) are attractive for therapeutics, especially the ability to manipulate these multipurpose entities. Various synthetic nanocarriers are used to deliver TNAs, but their clinical translation is limited due to immunotoxicity. Exosomes are cell-derived nanovesicles involved in cellular communication. Due to their ability to deliver biomolecules, exosomes are a novel delivery choice. In this study, researchers at System Biosciences explored the exosome-mediated delivery of NANPs to target GFP. They assessed the intracellular uptake, gene silencing efficiency, and immunostimulation of exosomes loaded with NANPs. They confirmed that interdependent RNA/DNA fibers upon binding to each other after delivery, can conditionally activate NF-kB decoys to prevent pro-inflammatory cytokines. This study overcomes challenges in TNA delivery and demonstrates future studies in drug delivery systems.