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31 reviewsIntracellular delivery of protein and RNA therapeutics represents a majorchallenge. Here, we develop highly potent engineered extracellular vesicles(EVs) by incorporating bio-inspired attributes required for effective delivery.These comprise an engineered mini-intein protein with self-cleavage activityfor active cargo loading and release, and fusogenic VSV-G protein for endosomal escape. Combining these components allows high efficiency recombination and genome editing in vitro following EV-mediated delivery of Crerecombinase and Cas9/sgRNA RNP cargoes, respectively. In vivo, infusion of asingle dose Cre loaded EVs into the lateral ventricle in brain of Cre-LoxP R26-LSL-tdTomato reporter mice results in greater than 40% and 30% recombinedcells in hippocampus and cortex respectively. In addition, we demonstratetherapeutic potential of this platform by showing inhibition of LPS-inducedsystemic inflammation via delivery of a super-repressor of NF-ĸB activity. Ourdata establish these engineered EVs as a platform for effective delivery ofmultimodal therapeutic cargoes, including for efficient genome editing.