Tumor microenvironment-responsive manganese nanocarriers for on-demand release of methotrexate and DNAzyme in...

Cervical cancer is a prevalent form of cancer that affects women on a global scale. MicroRNA-155 (miR-155) has been identified as a key player in cervical cancer, with its over-expression signifying a promising target for therapeutic interventions. However, the molecular mechanisms by which miR-155 contributes to the invasive progression of cervical cancer, as well as miRNA-based therapeutic approaches, remain to be elucidated. To address the issues, we initially investigated the functional role of miR-155 in cervical cancer progression. In vitro and in vivo results demonstrated that miR-155 was closely associated with the malignant progression of cervical cancer through regulation of the epithelial-mesenchymal transition (EMT) process, specifically by directly targeting ZFPM2 protein, thereby exerting oncogenic effects. Based on these findings, we designed manganese-based composite agents, namely MnO₂@PDA-DNAzyme-substrate-methotrexate nanoparticles (MPDM NPs), for simultaneous miRNA imaging and chemotherapy toward cervical cancer. The MPDM NPs exhibited favorable biocompatibility and tumor microenvironment (TME) responsive release behavior, allowing controlled release of Mn²⁺, methotrexate (MTX), and DNAzyme probes for miR-155 detection and therapeutic intervention. In vivo studies with tumor-bearing mice indicated that the MPDM NPs could effectively target tumors. The Mn²⁺-activate miRNA imaging achieved a detection limit for miR-155 of 0.3 nM. Moreover, the drug MTX enabled tumor chemotherapy by regulating the EMT process. This, in turn, has resulted in an impressive tumor inhibition rate of 86.2%. This proposed strategy indicated significant potential for the advancement of precision theranostics in the context of cervical cancer.