Triple‐Layered Metal‐Organic Framework Hybrid for Tandem Response‐Driven Enhanced Chemotherapy

Abstract 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 H 2 O 2 ‐responsive coordination complex shell of Fe 3+ and eigallocatechin gallate (EGCG). In the tumor microenvironment, the shell was dissociated by endogenous H 2 O 2 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.