Engineered a Gemcitabine Nano‐Prodrug Targeting Desmoplastic Pancreatic Tumor with Dual Enhancement of Penetration Dynamics

Abstract The desmoplastic nature characterized by dense tissue and poor vascular conditions in pancreatic cancer (PDAC) poses a significant barrier to effective chemotherapy. Targeting the extracellular matrix and reducing desmoplasia in the tumor microenvironment is a rational approach to improve the penetration and efficacy of gemcitabine (GEM) in PDAC. Herein, a small molecular self‐assembly nano‐prodrug is developed for the “three‐in‐one” co‐delivery of GEM chemotherapeutics, all‐trans retinoic acid (ATRA), and nitric oxide (NO) donors, decorated with PDAC‐homing targeting peptide. Stimulated by the PDAC microenvironment, the nano‐prodrug releases ATRA that quiesces activated pancreatic stellate cells to alleviate stromal desmoplasia. Simultaneously, it generates abundant NO to induce a vasodilatory effect as well as a “nanomotor” effect. This combinational nano‐prodrug delivery strategy, with a dual enhancement of drug penetration dynamics, effectively improves the distribution and bioavailability of the co‐delivered GEM into the deep and dense pancreatic tumor tissue, which leads to significant amplification of tumor growth inhibition in different PDAC mouse models.