This study demonstrates a paracrine mechanism for EVs secretion mediated by Rab5B‐CD109 interplay in KRAS‐mutant pancreatic cancer, which triggers targeted delivery of circPNIT through CD109+EVs to neurons, thus promoting tumor‐associated axonogenesis and PNI, highlighting the CD109+ EV‐packaged circPNIT as an effective target for early intervention of PDAC patients with PNI. This evidence concerns the gene CD109 and pancreatic neoplasm.