ABSTRACT: The promise of Interleukin-12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL-12ª, a novel, engineered-exosome therapeutic that displays functional IL-12 on the surface of an exosome. IL-12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN resulting in equivalent potency in vitro to recombinant IL-12 (rIL-12) as demonstrated by IFN_ production. Following intratumoral injection, exoIL-12 exhibited prolonged tumor retention and greater antitumor activity than rIL-12. Moreover, exoIL-12 was significantly more potent than rIL-12 in tumor growth inhibition. In the MC38 model, complete responses were observed in 63% of mice treated with exoIL-12; in contrast, rIL-12 resulted in 0% complete responses at an equivalent IL-12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Re-challenge studies of exoIL-12 complete responder mice showed no tumor regrowth and depletion of CD8+ T cells completely abrogated antitumor activity of exoIL-12. Following intratumoral administration, exoIL-12 exhibited 10-fold higher intratumoral exposure than rIL-12 and prolonged IFN_ production up to 48 hr. Retained local pharmacology of exoIL-12 was further confirmed using subcutaneous injections in non-human primates. This work demonstrates that tumor-restricted pharmacology of exoIL-12 results in superior in vivo efficacy and immune memory without systemic IL-12 exposure and related toxicity. ExoIL-12 is a novel cancer therapeutic candidate that overcomes key limitations of rIL-12 and thereby creates a therapeutic window for this potent cytokine.