Molecular machines drive smart drug delivery.

mechanical stress. The diameters of the pores can be tuned between 2 and 10 nm to allow for different drug loadings. Compared with traditional oral or injectable drugs, these meso­ porous nanoparticles can enhance bioavailabil­ ity, improve therapeutic efficacy and minimize side effects [4]. At present, the key challenge in developing mesoporous nanoparticle­based DDS is designing the structure and surface properties of these nanoparticles to enable the targeted, on­demand release of drug molecules. Molecular machines (e.g., rotaxanes, pseu­ dorotaxanes and azobenzenes) are capable of delivering efficient actuations at dramatically reduced length scales when compared with tra­ ditional microscale actuators [5–10]. Their ability to precisely and cooperatively control mechani­ cal motions at the molecular level, in addition to their comparable sizes to the mesopores of nanoparticles, makes molecular machines prime candidates for controlled release systems in mesoporous nanoparticle­based drug delivery. Molecular machines are enabling timed and controlled release of therapeutic compounds from the mesoporous nanoparticles upon vari­ ous forms of external stimuli, such as chemi­ cal reduction/oxidation, light, magnetic fields, enzymes and changes in the surrounding pH [11]. This area of research is swiftly maturing with the progress in synthesis, surface function­ alization, operation and characterizations of molecular machines. To fulfill their potential in DDS, molecular machines must retain the switching capabil­ ity and full range of mechanical motion when transferred from solution to nanoparticle sur­ faces. Extensive research on molecular machines assembled on metallic nanoparticles reveals multiple effects of surface confinement on the switching and motions of molecular machines, In his historic lecture to the American Physical Society in 1959, ‘There is plenty of room at the bottom’, Richard Feynman, one of the greatest scientists of the 20th Century, shared a futur­ istic vision with his audience using molecular machines in medicine. He contemplated, “What would be the utility of such (molecular­scale) machines? ... Although it is a very wild idea, it would be interesting in surgery if you could swallow the surgeon. You put the mechanical surgeon inside the blood vessel and it goes into the heart and ‘looks’ around. It finds out which valve is the faulty one and takes a little knife and slices it out. Other small machines might be per­ manently incorporated in the body to assist some inadequately functioning organ” [1]. As of today, the small machine­powered surgeon predicted by Feynman has yet to be realized; however, the idea of using molecular­level machines in nanomedi­ cine is burgeoning just as predicted [2,3]. Thus far, scientists have made significant progress in devel­ oping molecular­machine­driven, mesoporous nanoparticle­based smart drug delivery systems (DDS) that are capable of timely, on­demand drug release. By combining the robustness of mesoporous nanoparticles and the preciseness of molecular machines, these smart DDS hold great promise for future nanotechnology­based medical therapy and treatment.