Irinotecan hydrochloride (CPT-11) based nanomedicines have entered the field of clinical treatment in pancreatic cancer due to the limited efficacy of CPT-11 as well as the grim situation of pancreatic cancer. Excipient-free nanomedicines have a better prospect as the waiver of certain carriers may simplify the clinical translation. We hypothesize that our fabricated excipient-free nanodispersions will have powerful therapeutic potential for pancreatic cancer. Herein we found that stronger cytotoxicity from our nanodispersions with better sensitivity induced more apoptosis of pancreatic cancer cells in vitro. Besides, these nanodispersions significantly suppressed tumor growth in mice bearing cell line derived xenografts both subcutaneously and orthotopically with at least similar effect with CPT-11. Considering CPT-11 functioning poorly in patients though well in mice and carboxylesterase being the key enzyme that differed a lot between them, we employed a carboxylesterase inhibitor to mimic carboxylesterase inadequacy in clinical situations. It turned out that CPT-11 was partially invalid under this circumstance while our fabricated excipient-free nanodispersions could still function well and prolong the overall survival significantly. These results collectively demonstrate that our excipient-free nanodispersions have powerful therapeutic potential for pancreatic cancer with a good prospect for clinical translation.