Re(I)-Based Molecular Actuator-Equipped Nanomotors for Integrated Photodynamic and Photomechanical Therapy of Solid Tumor

The dense stromal barrier of solid tumors severely hinders intratumoral distribution and therapeutic performance of conventional nanomedicines, and such limitation further compromises oxygen-dependent photodynamic therapy. Herein, through molecular engineering, we develop a Janus nanomotor (Re1@NMs) that integrates a three-dimensional rhenium(I)-based molecular actuator (Re1) with glucose oxidase (GOx)-powered propulsion. Owing to the Janus structure, asymmetric GOx-catalyzed glucose consumption generates local chemical gradients that fuel autonomous motility, thereby enhancing intratumoral distribution. Upon light activation, the engineered Re1, screened from six Re(I) complexes, functions both as a dual Type I/II photosensitizer generating reactive oxygen species (ROS) to induce oxidative stress and as a molecular actuator whose Y-axis motif undergoes E/Z photoisomerization and torsional deformation, thereby contributing to membrane permeabilization. The resulting integrated mechano-photodynamic action coordinately activates ferroptosis and pyroptosis. In a murine tumor model, Re1@NMs-mediated phototherapy achieves superior tumor suppression with excellent biosafety and further elicits robust antitumor immunity, as evidenced by enhanced dendritic cell maturation, increased tumor-infiltrating T cells, elevated effector cytokine expression, and damage-associated molecular pattern release. To the best of our knowledge, this work represents the first integration of a deliberately engineered metal-complex-based three-dimensional molecular actuator with a tumor-microenvironment-adaptive nanomotor, establishing a new paradigm for overcoming tumor barriers.