Glucose-Fueled Gated Nanomotors: Enhancing <i>In Vivo</i> Anticancer Efficacy via Deep Drug Penetration into Tumors

Bioinspired nano/micromotors with drug delivery capabilities are emerging tools with the promising potential to treat numerous diseases. However, some major challenges must be overcome before reaching real biomedical applications. Above all, it is necessary to design engines that employ biocompatible and bioavailable fuels to induce efficient propulsion in biological environments. In addition, ideal nanomotors should also be capable of delivering the cargo on-command using selected stimuli. To tackle these challenges, we herein present the design and evaluation (both <i>in vitro</i> and <i>in vivo</i>) of a glucose-driven gated Janus nanomotor that performs on-demand anticancer drug delivery to treat solid tumors. The motor's nanoarchitectonics is based on the anisotropic conjunction of catalytic platinum nanodendrites (PtNds) and a mesoporous silica nanoparticle (acting as a nanocontainer for anticancer drug doxorubicin) capped with enzyme glucose oxidase (GOx). Autonomous nanomotor movement is achieved thanks to two catalytic components, GOx and PtNds, in a hybrid cascade reaction: GOx transforms glucose to give H₂O₂ that is subsequently catalyzed by PtNds into H₂O and O₂. Besides, gatekeeper moieties (GOx) respond to the presence of intracellular proteases, which induces doxorubicin delivery. Biological experiments with the nanomotor are carried out in cancer cell cultures, three-dimensional (3D) tumor models (spheroids), <i>in vivo</i> and in patient-derived organoids (PDOs). A strong anticancer effect is found and attributed to the synergistic combination glucose-induced propulsion, controlled drug delivery, elimination of glucose (by GOx), ROS production (H₂O₂ generation by GOx) and hypoxia reduction (O₂ generated by PtNds). Taken together, this study advances the engineering of endogenously fueled nanomotors for <i>in vivo</i> operation and provides insights into the application of active particles in cancer therapy toward clinical application.