Chen, Kuan-HungKuan-HungChenNguyen, NhienNhienNguyenHuang, Tun-YuTun-YuHuangLin, Yu-JungYu-JungLinYu, Yu-TzuYu-TzuYuHSIANG-LIN SONGWang, Jui-ToJui-ToWangNguyen, Van KhanhVan KhanhNguyenChen, Hsin-LungHsin-LungChenChu, Li-AnLi-AnChuChiang, Hui-Hua KennyHui-Hua KennyChiangSung, Hsing-WenHsing-WenSung2023-12-052023-12-052023-1009359648https://scholars.lib.ntu.edu.tw/handle/123456789/637504The prognosis in cases of pancreatic ductal adenocarcinoma (PDAC) with current treatment modalities is poor owing to the highly desmoplastic tumor microenvironment (TME). Herein, a β-glucans-functionalized zinc-doxorubicin nanoparticle system (βGlus-ZnD NPs) that can be orally administered, is developed for targeted PDAC therapy. Following oral administration in PDAC-bearing mice, βGlus-ZnD NPs actively target/transpass microfold cells, overcome the intestinal epithelial barrier, and then undergo subsequent phagocytosis by endogenous macrophages (βGlus-ZnD@Mϕ). As hitchhiking cellular vehicles, βGlus-ZnD@Mϕ transits through the intestinal lymphatic system and enters systemic circulation, ultimately accumulating in the tumor tissue as a result of the tumor-homing and "stealth" properties that are conferred by endogenous Mϕ. Meanwhile, the Mϕ that hitchhikes βGlus-ZnD NPs is activated to produce matrix metalloproteinases, destroying the desmoplastic stromal barrier, and differentiates toward the M1 -like phenotype, modulating the TME and recruiting effector T cells, ultimately inducing apoptosis of the tumor cells. The combination of βGlus-ZnD@Mϕ and immune checkpoint blockade effectively inhibits the growth of the primary tumor and suppresses the development of metastasis. It thus represents an appealing approach to targeted PDAC therapy.endesmoplastic stromal barrier; immune checkpoint blockade; intestinal epithelial barrier; macrophage hitchhiking; tumor microenvironmentjournal article10.1002/adma.202304735373638862-s2.0-85168114232https://api.elsevier.com/content/abstract/scopus_id/85168114232