Senescent cells accumulate in multiple aging‐associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β‐galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto‐oligosaccharides. We show that gal‐encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy‐induced senescence, gal‐encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. Moreover, in a model of pulmonary fibrosis in mice, gal‐encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, gal‐encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence‐associated disorders.

A new gated nanodevice design able to control cargo delivery using glucose as trigger and cyclodextrin-modified glucose oxidase as capping agent is reported.Mass transport control at the nanometric level is a captivating area of research that has attracted the attention of scientists in the latest years. Especially, the development of gated systems able to retain a cargo and release it after the application of a stimulus has demonstrated to be an excellent approach for the development of smart nanodevices for advanced delivery applications. 1 In this context, silica mesoporous supports are widely used as inorganic scaffolds thanks to their unique characteristics such as high homogeneous porosity, inertness, robustness, thermal stability, the presence of tunable pore sizes, homogeneous pore distribution and high loading capacity. 2 Moreover, via decoration of the mesoporous material with a wide collection of organic moieties, linkers and capping agents, researchers have prepared nanovalves that can be triggered with target chemical 3 (such as redox molecules, selected anions, pH changes and biomolecules) physical 4 (such as light, temperature or magnetic fields) and biochemical (such as enzymes, antibodies, or DNA) stimuli. 5 In particular the development of enzyme-responsive bio-gated mesoporous silica nanoparticles is appealing. In previously reported examples tailor-made sequences anchored on the mesoporous support are hydrolized by target enzymes allowing the selective release of the entrapped cargo. However in these cases enzymes act as triggers but as far as we know there are not examples where enzymes were used as functional gating elements. 6 In this context, and as a new approach, we envisioned the potential design of gated materials in which the enzymes could act as caps and the uncapping process would be triggered by the product obtained by the enzyme's activity on a target substrate. The combination of the promising features of silica mesoporous supports as containers, enzymes as caps and substrates as trigger would result in a sophisticated but simple way to prepare selective substrate-responsive gated mesoporous materials for different applications. As a proof-of-concept we have selected herein glucose oxidase as capping enzyme and glucose as the substrate to trigger cargo release.The designed capped support is depicted in Scheme 1. It is based on the use of mesoporous silica nanoparticles loaded with a suitable reporter (i.e. ruthenium bipyridine complex) and containing anchored methylbenzymidazole moieties on the pore outlets. The mesopores are then capped with an active CDmodified-glucose oxidase (CD-GOx) through the formation of an inclusion complex between the cyclodextrins and the propylbenzymidazole group anchored to the solid support. The presence of the substrate glucose combined with the catalytic action of CD-GOx to produce gluconic acid was expected to induce protonation of the benzymidazole group that might result in the inclusion complex dethreating and the subsequent cargo release. Sc...