Extracellular vesicles (EVs) can transport functional RNA, but the clinical development of EV-based RNA therapeutics has been constrained by the technical demands of ex vivo production and cargo loading. A recently reported strategy uses a plasmid to direct the formation of small interfering RNA (siRNA)-containing small EVs (sEVs) in vivo. Following administration, hepatocytes produce the therapeutic RNA and release it in association with endogenous sEVs, allowing systemic delivery to be achieved without isolating and reloading vesicles outside the body. This commentary examines the biological basis and potential therapeutic relevance of this approach. Particular attention is given to endogenous cargo loading, the use of genetically encoded targeting peptides to alter vesicle distribution, and the experimental issues that remain before clinical translation can be considered. These issues include control of vesicle composition, definition of the delivered dose, formulation-related toxicity, and the effects of repeated administration.