Spatially Selective\nSelf-Amplified Imaging of Chemotherapy-Induced\nCancer Senescence via Reversal of Impaired Ferritinophagy

Real-time monitoring of chemotherapy-induced senescence\n(CIS) in\ncancer remains a challenging task that would lead to new insights\ninto the adaptive mechanisms of cancer therapy and provide guidance\nfor cancer management. Here, we designed a tailor-made nanoprobe capable\nof imaging CIS in a sequential activation and self-amplified manner\nby reversing senescence-related impaired ferritinophagy. It contains\nan amphipathic polymer as a spatially responsive vehicle, a Fe<sup>2+</sup>-activable dye as the reporter, and an autophagy inducer\nas the signal amplifier. Owing to metabolic changes, the nanoprobe\npreferentially enriches in senescent cancer cells, leading to in situ\nactivation and fluorescence switching of the reporter by labile Fe<sup>2+</sup>. Meanwhile, the inducer restores ferritinophagy and promotes\nautophagic degradation of accumulated ferritin, facilitating conversion\nof ferritin-bound iron into Fe<sup>2+</sup> for amplified imaging\nin senescent cancer cells yet keeping inert in nonsenescent cells.\nOf note, the accumulation and activation of the nanoprobe and sustained\nferritin degradation occur at the same subcellular location, thus\nminimizing the diffusion process-induced nonspecific responses. The\nfeasibility of this strategy is successfully demonstrated in both\nliving cells and animal models. This work offers a new way for therapeutic\nevaluation and a basic understanding of the roles of senescence in\ncancer treatment.