Drug Delivery Platform Targeting MMP9 in Combination with Photothermal Therapy to Improve Tumor Chemosensitivity

Abstract Tumor chemotherapy insensitivity poses a significant challenge in cancer treatment, with angiogenesis being a key contributing factor. Angiogenesis supplies oxygen and nutrients to tumor cells, thereby impairing treatment outcomes. Based on these findings, an MMP9‐responsive carbon quantum dot‐based nanoplatform (MMP9i@MTX@CQDs) encapsulating methotrexate (MTX) and an MMP9 inhibitor (MMP9i) is developed to overcome chemotherapy insensitivity. Targeting the high expression of MMP9 in tumors, the platform releases its payload in a responsive manner. Under near‐infrared (NIR) irradiation, the system effectively downregulated angiogenesis‐related molecules, including VEGF and CD31, and inhibited the Wnt/β‐catenin signaling pathway, thereby reversing chemotherapy insensitivity. This nanoplatform integrates MMP9‐responsive CQDs with MTX, enabling photothermal therapy (PTT) and MMP9 inhibition, offering a robust and safe strategy to sensitize tumors to chemotherapy.