Aggressive solid tumors such as triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma are rarely driven by a single dominant oncogene. Instead, their malignant behavior emerges from densely interconnected signaling networks, a complexity that has frustrated many single-target therapeutic strategies. In this issue of Molecular Therapy, Tossou and colleagues identify a 15-microRNA (miRNA) signature (miR-Comb 15) functionally linked to the transcription factor NFAT3 (NFATc4) that collectively recapitulates the anti-tumoral activity of NFAT3-regulated extracellular vesicles (EVs), and they engineer a scalable HEK293T-derived EV platform to deliver it (Figure 1).