Reversibly controlling the dye arrangements in living systems has great potential to realize spatiotemporally controlled photomedicine. However, tuning or even maintaining a certain arrangement of dyes in a complex living environments is extremely challenging due to the interference of the various biological species. Herein, a conceptual supramolecular strategy to engineer a switchable photosensitizer (PS) via mitochondria-mediated dynamic interconversion between monomer and J-aggregation, enabling specific activation of the mitochondria-targeting photodynamic therapy (PDT) and hibernation after mitochondria damage is presented. The presented mitochondria-mediated "activate-then-hibernate" PS design enables a fascinating spatiotemporally controlled PDT in which spatially controlled mitochondrial-targeting enhances therapeutic efficacy and temporally controlled activation-then-hibernation averts off-target damage during PDT and tissue damage after clinical treatment, thus offering significant potential for biological research and clinical needs.