Adaptive Size Evolution of an MOFs-in-MOF Nanovehicle\nfor Enhanced Nucleus-Targeted Tumor Chemotherapy

A metal–organic\nframeworks (MOFs)-in-MOF nanovehicle (160\nnm), which was constructed with newly prepared ultrasmall Cu(I)Cu(II)-BTC\nMOFs (UCMs, 2.95 nm) loaded with doxorubicin (DOX) and a nuclear localization\nsignal (NLS) peptide as multicores (UCMDNs) and ZIF-8 as the shell\nMOF, was proposed to cross layers of biological barriers with adaptive\nsize evolution capacity for achieving efficient nucleus-targeted drug\ndelivery. It first enhanced tumor tissue penetration through its larger\nnanosize effect. Then the acidic tumor environment made the ZIF-8\nshell degrade, releasing small-sized UCMDNs to enter into the cell\nand into the nucleus under the guidance of NLS. Furthermore, due to\nthe distinct surface structural characteristics of UCMs, UCMDNs remained\nstable in the cytoplasm and collapsed in the nucleus due to the DOX–DNA\ninteraction to deliver DOX precisely. It showed superior performance\nin the nucleus-directed delivery of DOX (delivery efficiency up to\n56.7%) and a high tumor growth inhibition rate (96.4%), offering promising\nprospects in tumor chemotherapy.