Older ages are intimately associated with various co-morbidities, including neurodegenerative, cardiovascular, and musculoskeletal pathologies. The tissues associated with these diseases commonly contain an accumulation of senescent cells, which have been considered a significant contributor to age-related tissue dysfunction. The elimination of these cells has been shown to suppress the development of these age-associated pathologies, thus presenting senescence as a potential clinical target. Senolytics are compounds, ranging from small molecules to larger nanoparticles, that have been shown to selectively target senescent cells. However, many of the reported systems lack post-administration regulation, which prevents precise spatiotemporal control. The established nanoparticle systems are also commonly polydisperse, which results in variable activity that can pose problems for therapeutic application or fundamental study of its interaction with senescent environments. In this work, a fullerene-BODIPY dyad with a senescent-responsive glycosidic bond was designed and characterized. The glycosidic bond is cleaved in the presence of beta-galactosidase, an enzyme commonly found to be up-regulated in senescent cells. Absorbance measurements illustrated a red-shifted absorbance band of the cleaved dyad compared to the non-cleaved dyad, exhibiting its ability to discern between senescent and normal environments. This system represents an energy-donor pairing that was shown to selectively generate cytotoxic ROS in senescent cells under irradiation. Such light-controlled activity bestows greater spatiotemporal regulation; furthermore, the application of a fullerene scaffold allows for the synthesis of a molecularly exact nanoparticle. The fullerene-BODIPY dyad exhibited suppressed activity in non-senescent cells as well as in non-irradiated, stress-induced senescent cells. Under irradiation, the cytotoxic activity of the dyad was selectively observed in senescent cells and remained inactive in normal cells. Furthermore, spatial and temporal variations of light exposure demonstrated precise post-incubation regulation.

Phototriggered elimination of senescent cells via fullerene-BODIPY dyad

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