Enzyme-Powered Gated Mesoporous Silica Nanomotors for On-Command Intracellular Payload Delivery

[EN] The introduction of stimuli-responsive cargo release capabilities on self-propelled micro- and nano- motors holds enormous potential in a number of applications in the biomedical field. Herein, we report the preparation of mesoporous silica nano-particles 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)]Cl-2 (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)]Cl-2 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.A.L.-L. is grateful to La Caixa Banking Foundation for his Ph.D. grant. A.G.-F. thanks the Spanish government for her FPU fellowship. The authors are grateful to the Spanish Government (MINECO Projects MAT2015-64139-C4-1, CTQ2014-58989- PCTQ2015-71936-REDT, CTQ2015-68879-R (MICRODIA) and CTQ2015-72471-EXP (Enzwim)), the BBVA foundation (MEDIROBOTS), the CERCA Programme by the Generalitat de Catalunya, and the Generalitat Valenciana (Project PROMETEO/2018/024 and PROMETEOII/2014/061) for support. T.P. thanks MINECO for the Juan de la Cierva postdoctoral fellowship and the European Union's Horizon 2020 research and innovation program, under the Marie Sk¿odowska-Curie Individual Fellowship (H2020-MSCA-IF2018, DNA-bots). A.C.H. thanks MINECO for the Severo Ochoa fellowship. The authors would like to thank A. Miguel Lopez for the development of the python code for motion analysis.Llopis-Lorente, A.; García-Fernández, A.; Murillo-Cremaes, N.; Hortelao, A.; Patiño, T.; Villalonga, R.; Sancenón Galarza, F.... (2019). Enzyme-Powered Gated Mesoporous Silica Nanomotors for On-Command Intracellular Payload Delivery. ACS Nano. 13(10):12171-12183. https://doi.org/10.1021/acsnano.9b067061217112183131