MRI-enabled ferroptosis self-amplifying nanoplatform synergizes with photothermal therapy to enhance chemotherapeutic efficacy against pancreatic cancer.

Abstract

Pancreatic cancer responds poorly to conventional chemotherapy, largely because of the pronounced resistance of tumor cells to chemotherapy-induced apoptosis. Ferroptosis, a non-apoptotic form of programmed cell death, has emerged as a promising strategy to overcome this resistance. However, its therapeutic efficacy is often limited by insufficient hydrogen peroxide (H₂O₂) and excessive glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a nanoplatform, HM-MnO₂@DOX/CaO₂@PDA/HA (HMDCPH), using hollow mesoporous manganese dioxide (HM-MnO₂) as a carrier to co-deliver doxorubicin (DOX) and calcium peroxide (CaO₂). The crosslinked PDA/HA shell enhanced both the tumor-targeting capability and biocompatibility of the nanoplatform. In the TME, HM-MnO₂ depleted GSH and promoted reactive oxygen species (ROS) generation, whereas CaO₂ decomposition generated H₂O₂ and released Ca²⁺, inducing mitochondrial calcium overload and further aggravating oxidative stress. These synergistic effects enhanced lipid peroxidation (LPO) and exacerbated ferroptosis-related oxidative damage. Moreover, the near-infrared (NIR)-triggered photothermal effect further strengthened the antitumor efficacy of HMDCPH. In addition, nanoplatform degradation released Mn²⁺, enabling T₁-weighted magnetic resonance imaging (MRI). Collectively, this study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.