The introduction of stimuli-responsive cargo release capabilities on self-propelled micro- and nanomotors holds enormous potential in a number of applications in the biomedical field. Herein, we report the preparation of mesoporous silica nanoparticles gated with pH-responsive supramolecular nanovalves and equipped with urease enzymes which act as chemical engines to power the nanomotors. The nanoparticles are loaded with different cargo molecules ([Ru­(bpy)3]­Cl2 (bpy = 2,2′-bipyridine) or doxorubicin), grafted with benzimidazole groups on the outer surface, and capped by the formation of inclusion complexes between benzimidazole and cyclodextrin-modified urease. The nanomotor exhibits enhanced Brownian motion in the presence of urea. Moreover, no cargo is released at neutral pH, even in the presence of the biofuel urea, due to the blockage of the pores by the bulky benzimidazole:cyclodextrin-urease caps. Cargo delivery is only triggered on-command at acidic pH due to the protonation of benzimidazole groups, the dethreading of the supramolecular nanovalves, and the subsequent uncapping of the nanoparticles. Studies with HeLa cells indicate that the presence of biofuel urea enhances nanoparticle internalization and both [Ru­(bpy)3]­Cl2 or doxorubicin intracellular release due to the acidity of lysosomal compartments. Gated enzyme-powered nanomotors shown here display some of the requirements for ideal drug delivery carriers such as the capacity to self-propel and the ability to “sense” the environment and deliver the payload on demand in response to predefined stimuli.

Development of bioinspired nanomachines with an efficient propulsion and cargo-towing has attracted much attention in the last years due to their potential biosensing, diagnostics, and therapeutics applications. In this context, self-propelled synthetic nanomotors are promising carriers for intelligent and controlled release of therapeutic payloads. However, the implementation of this technology in real biomedical applications is still facing several challenges. Herein, we report the design, synthesis, and characterization of innovative multifunctional gated platinum–mesoporous silica nanomotors constituted of a propelling element (platinum nanodendrite face), a drug-loaded nanocontainer (mesoporous silica nanoparticle face), and a disulfide-containing oligo(ethylene glycol) chain (S–S–PEG) as a gating system. These Janus-type nanomotors present an ultrafast self-propelled motion due to the catalytic decomposition of low concentrations of hydrogen peroxide. Likewise, nanomotors exhibit a directional movement, which drives the engines toward biological targets, THP-1 cancer cells, as demonstrated using a microchip device that mimics penetration from capillary to postcapillary vessels. This fast and directional displacement facilitates the rapid cellular internalization and the on-demand specific release of a cytotoxic drug into the cytosol, due to the reduction of the disulfide bonds of the capping ensemble by intracellular glutathione levels. In the microchip device and in the absence of fuel, nanomotors are neither able to move directionally nor reach cancer cells and deliver their cargo, revealing that the fuel is required to get into inaccessible areas and to enhance nanoparticle internalization and drug release. Our proposed nanosystem shows many of the suitable characteristics for ideal biomedical destined nanomotors, such as rapid autonomous motion, versatility, and stimuli-responsive controlled drug release.