Proton Sponge‐Enabled Dual‐Driven Nanomotors for MRI‐Guided Tumor‐Penetrating Synergistic Therapy of Pancreatic Cancer

ABSTRACT Dense stromal barriers and lysosomal sequestration severely restrict the extracellular transport and intracellular trafficking of nanomedicines in pancreatic cancer, while the robust glutathione (GSH)‐dependent antioxidant defense further compromises therapeutic efficacy. Here, we developed a proton sponge‐enabled dual‐driven nanomotor, HA/PEI‐DOX@MMSN@Pt (HPDMP), for MRI‐guided pancreatic cancer therapy. The asymmetric Pt domain generated near‐infrared (NIR)‐induced self‐thermophoretic motion as the principal externally controllable driving mechanism, whereas endogenous H 2 O 2 provided auxiliary catalytic propulsion, together facilitating nanomotor transport through the dense tumor stroma and enhancing intratumoral penetration. Following cellular uptake, PEI‐mediated proton sponge activity facilitated lysosomal escape and increased cytosolic DOX availability. Meanwhile, tumor‐microenvironment‐responsive degradation of the Mn‐doped framework consumed GSH and released Mn 2+ , thereby enhancing reactive oxygen species (ROS) generation, ferroptosis‐associated oxidative damage, and T 1 ‐weighted MRI contrast. HA modification further promoted CD44‐mediated tumor targeting. Under NIR irradiation, HPDMP achieved pronounced antitumor efficacy with favorable biosafety. This work provides a barrier‐oriented nanomotor strategy for pancreatic cancer therapy.