Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)­phenyl-2,4-dinitrobenzenesulfonate and Fe³⁺ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.