Cerenkov radiation modulates the extracellular matrix for improved pancreatic cancer chemotherapy

<h2>Summary</h2> Abundant cancer-associated fibroblasts (CAFs) in pancreatic tumors cause robust interstitial fibrosis and abnormal vascular structure, hindering the delivery and effectiveness of small-molecule therapeutics, leading to poor clinical outcomes. We developed a strategy to modulate the extracellular matrix (ECM) in pancreatic cancer to enhance chemotherapy through sequential administration of TiO₂ nanoparticles (NPs), [⁶⁸Ga]Ga-FAPI-04 ([⁶⁸Ga]Ga-FAPI), and the chemotherapeutic drug tirapazamine (TPZ). The positron emission tomography tracer [⁶⁸Ga]Ga-FAPI specifically targets CAFs and serves as an internal excitation source for Cerenkov radiation-mediated photodynamic therapy (CR-PDT). TiO₂ NPs generate cytotoxic reactive oxygen species upon CR, destroying tumor cells and CAFs. As a result, CR-PDT reduces the dense stromal barrier by inhibiting the formation and secretion of fibrous collagen, improving the delivery of TPZ. Additionally, CR-PDT consumes oxygen throughout the process, intensifying tumor hypoxia, which further activates TPZ, a hypoxia-activated and bio-reductive prodrug. Our design of CR-PDT-mediated ECM modulation brings new ideas for the exploration and application of radiotracer-combined nanomedicine in cancer therapy, particularly for cancers with abundant ECM.