Dual‐Driven Janus Nanomotors Combined with a Size‐Shrinkage Strategy for Enhanced Tumor Penetration and Synergistic Chemo/Photothermal/Photodynamic Therapy

Abstract Further applications of nanotherapeutic systems are greatly hindered by their unsatisfactory tumor permeability. Therefore, achieving an optimal balance between long circulation time and deep penetration is imperative. Janus nanomotors have garnered significant attention owing to their distinctive asymmetric structure and exceptional active motility. Herein, a novel doxorubicin (DOX)‐loaded and glucose oxidase (GOx)‐modified Janus mesoporous organosilica‐AuPt nanomotor encapsulated in a metal–organic framework (MOF), namely DOX/GOx‐MSN‐AuPt@MOF, is developed for enhanced tumor penetration and synergistic chemo/photothermal/photodynamic therapy. In response to an acidic tumor microenvironment, the nanosystem underwent a process of size‐shrinkage from ≈170 to ≈40 nm, inducing the release of nanomotors. Nanomotors rely on excellent motility for deep penetration into tumors, driven by the combined action of a cascade reaction catalyzed by glucose oxidase‐AuPt, using glucose as fuel to produce oxygen, and thermal gradient generated by near‐infrared laser irradiation. Synergistic tumor treatment is achieved through the drug, DOX; reactive oxygen species generated during tandem catalysis; and localized high temperature. Effective aggregation, deep penetration, and outstanding anti‐tumor activity of the nanosystem are confirmed via 2D cells, 3D multicellular tumor spheroids, and tumor‐bearing mouse models. This study provides a new prospect for constructing a combined treatment system for deep tumor penetration.