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

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.