Oral delivery of a CD44-targeted polydopamine nanoplatform for synergistic chemo–chemodynamic colon cancer therapy: Preparation, characterization, and in vitro study

HA@PDA/Cu/DOX oral nanoplatform is designed for CRC synergistic CT/CDT therapy. • The nanosystem shows efficient DOX loading and sustained release to avoid premature leakage. • HA modification enhances the nanoplatform's mucus penetration ability. • The nanoplatform achieves CD44-mediated uptake and CT/CDT synergy against CT26 cells. • HA@PDA/Cu/DOX realizes deep intratumoral penetration in 3D colon tumor spheroids. Clinical outcomes in colorectal cancer (CRC) are frequently compromised by systemic toxicity and poor tumor targeting associated with conventional chemotherapy (CT) regimens. Herein, we rationally designed an oral colon-targeted nanoplatform, HA@PDA/Cu/DOX, for synergistic CT and chemodynamic therapy (CDT) to address these limitations. The system consists of a polydopamine (PDA) core that co-delivers doxorubicin (DOX) and copper ions, surface-functionalized with hyaluronic acid (HA) for CD44-mediated active targeting. Physicochemical characterization verified the successful preparation of the formulation, with DOX loading efficiency of 5.64 ± 0.42%, and a uniform size distribution. In vitro investigations showed that HA@PDA/Cu/DOX achieved sustained drug release, and displayed favorable mucus penetration (67.81%). HA-mediated targeting was observed to promote cellular uptake in CT26 cells, mainly through clathrin- and lipid raft/caveolae-dependent endocytosis. Meanwhile, Cu 2+ -catalyzed Fenton-like reactions were shown to generate reactive oxygen species (ROS) and deplete glutathione (GSH), thereby disturbing redox balance and sensitizing tumor cells to DOX. In addition, the nanosystem enabled deep penetration into 3D tumor spheroids (up to 72 μm) and exhibited cytotoxic effects, with CT26 cell viability below 15% at a DOX concentration of 5 μg/mL. This fabricated oral system combines colon-targeted delivery with gastrointestinal barrier penetration and synergistic CT/CDT therapy, exhibiting excellent in vitro antitumor performance and providing a feasible basis for subsequent in vivo verification and CRC treatment research. Download: Download high-res image (350KB) Download: Download full-size image