Distinguishing glutathione (GSH) level in different subcellular locations is critical for studying its antioxidant function in the signaling system. However, traditional methods for imaging subcellular GSH were achieved in isolated organelles or fixed cells. In this work, we report a quencher‐delocalized emission strategy for in situ profiling of GSH at different subcellular locations in living cells. A nonemissive metal–organic framework (MOF) nanoprobe was designed with AIEgen as the linker and CuII as the node and quencher. The AIEgen in MOF structure was lightened up with green emission in a neutral environment due to partial CuII delocalization by competitive binding to GSH. Meanwhile, along with the protonation of AIEgen ligand under acidic environment, the AIEgen‐based MOF could be completely dissociated in the presence of GSH to yield yellow emission. The two‐channel ratiometric analysis of dual‐colored emission of AIEgen‐based MOF allows visualization of GSH in cytoplasm and lysosome in living cells, which is also able to report the drug effects on different subcellular GSH levels.

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Ferroptosis, a nonapoptotic cell‐death pathway, is commonly regulated by ether lipid peroxide generation or glutathione consumption. In this work, a parallel lipid peroxide accumulation strategy was designed based on catalytic metal–organic frameworks (MOFs) for enhanced ferrotherapy. The bimetallic MOF was synthesized with iron porphyrin as a linker and cupric ion as a metal node, and erastin, a ferroptosis inducer, was sandwiched between the MOF layers with 4,4′‐dipyridyl disulfide as spacers. In a tumor microenvironment, erastin was released from the layered MOFs through glutathione‐responsive cleavage. The exfoliated MOFs served as a dual Fenton reaction inducer to generate numerous hydroxyl radicals for the accumulation of lipid peroxide, while erastin‐aggravated glutathione depletion down‐regulated glutathione peroxidase 4; this then inhibited the consumption of lipid peroxide. Therefore, a parallel lipid peroxide accumulation strategy was established for enhanced ferrotherapy that effectively inhibited tumor growth in live mice, opening up new opportunities to treat apoptosis‐insensitive tumors.

The precise release of drugs is essential to improve cancer therapeutic efficacy. In this work, a tandem responsive strategy was developed based on a triple‐layered metal‐organic framework (MOF) hybrid. The MOF nanoprobe was stepwise fabricated with a telomerase‐responsive inner, a pH‐sensitive MOF filling and H2O2‐responsive coordination complex shell of Fe3+ and eigallocatechin gallate (EGCG). In the tumor microenvironment, the shell was dissociated by endogenous H2O2 and simultaneously produced highly reactive hydroxyl radicals by a Fenton reaction. Meanwhile, the released EGCG could downregulate the expression of P‐glycoprotein responsible for drug resistance. After the dissociation of the framework by protons, telomerase could trigger the release of the drug from the DNA duplex on the exposed inner shell. By integrating confined drug release, inhibited efflux pump and chemodynamic therapy, the all‐in‐one chemotherapy strategy was identified with enhanced therapeutic efficacy in drug‐resistant cancer cells.