Abstract

Antitumor agent-109 (AA109) blocks CD44-HA interaction, mitigating gemcitabine (GEM) resistance induced by extracellular matrix (ECM) stiffening. • Mesoporous CuS (MCuS), a photothermal nanomaterial, co-delivers AA109 and GEM, achieving synergistic photothermal therapy (PTT)-chemotherapy for pancreatic ductal adenocarcinoma (PDAC) • Cancer cell membrane coating enhances tumor targeting and biosafety of the nanocarrier. Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis, where chemoresistance is closely linked to fibrotic extracellular matrix (ECM) remodeling. Hyaluronic acid (HA)-CD44 binding increases ECM stiffness and upregulates drug efflux protein ABCG2, exacerbating PDAC chemoresistance. Disrupting CD44-HA interaction is a promising strategy to overcome chemoresistance. Photothermal therapy (PTT) has high efficacy and low toxicity in cancer therapy, demonstrating notable synergy with chemotherapy. Methods MCuS@GEM@Antitumor agent-109@M (CGAM) nanoparticles were fabricated by coating mesoporous CuS (MCuS) loaded with AA109 and gemcitabine (GEM) using PDAC cell membranes. Physicochemical properties, photothermal conversion, and drug release were characterized via dynamic light scattering, UV–Vis spectroscopy, transmission/scanning electron microscopy, and thermal imaging. Hemocompatibility and anticancer efficacy were evaluated through hemolysis, cellular uptake, viability, live/dead staining, and apoptosis experiments. Flow cytometry and pancreatic patient-derived organoids fluorescence assays assessed CD44-HA blockade. A xenograft mouse model was established to examine biodistribution, antitumor efficacy, and biosafety. Results CGAM exhibited uniform size, stability, and efficient photothermal conversion. In vitro, CGAM combined with PTT effectively killed PANC-1 cells and disrupted CD44-HA binding. In vivo, CGAM selectively accumulated in tumors, significantly suppressing PDAC progression with favorable b