Calcipotriol-induced Stromal Remodeling Enhances Cell Membrane-Camouflaged Gemcitabine Delivery and Efficacy in Pancreatic Cancer

Gemcitabine remains the standard chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC); however, its efficacy is limited by poor tumor targeting and low permeability caused by the dense fibrotic stroma. To overcome these limitations, we developed an integrated dual-axis combinatorial strategy. We first constructed biomimetic cancer cell membrane-coated gemcitabine nanoparticles (CMG) and co-administered them with the vitamin D analogue calcipotriol (CAL). Both in vitro and in vivo studies demonstrated that PDAC cells preferentially internalized CMG via clathrin-mediated endocytosis, and CMG can enable sustained intratumoral drug release. Simultaneously, CAL activated the vitamin D receptor signaling pathway in cancer-associated fibroblasts (CAFs), modulatied the expression of fibrosis-related markers, and promoted CAFs to normal fibroblast then potentially enhancing nanoparticle penetration and therapeutic potential. Furthermore, mRNA sequencing, network pharmacology, and bioinformatic analyses comparing wild-type and gemcitabine-resistant PDAC cell lines identified the potential regulatory molecules implicated in CAL-improved chemoresistance, which were validated by structural dynamics and functional assays. In vivo, the CMG/CAL combined therapy significantly inhibited tumor growth while enhancing therapeutic efficiency. This integrated treatment approach rationally couples improved drug delivery with stromal remodeling, offering a promising avenue to overcome chemoresistance in PDAC.