Macrophage‐Hitchhiked Orally Administered β‐Glucans‐Functionalized Nanoparticles as “Precision‐Guided Stealth Missiles” for Targeted Pancreatic Cancer Therapy

Abstract The 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.