Developing Enzyme-Responsive Nanomedicine for Inhibition of hTERT Mitochondrial Translocation

Although considerable efforts have been made to increase the sensitivity of anticancer agents, few strategies have been found to show general effects. Human telomerase reverse transcriptase (hTERT) is overexpressed in the majority of cancer cells. hTERT has been demonstrated to translocate to mitochondria and promote cell survival under cell stress, leading to significant resistance to chemotherapeutics in various cancer cells. Thus, inhibition of hTERT translocation from nuclei to mitochondria may be developed as an effective and general way to improve drug sensitivity. Herein, leptomycin B (LMB, a nuclear export inhibitor of hTERT) and doxorubicin are delivered into cancer cells by a mesoporous silica nanocarrier. This straightforward design can inhibit hTERT translocation and improve drug chemosensitivity in different types of cancer cells. Mechanism studies reveal that hTERT movement inhibition perturbs the protection of hTERT to mitochondria, exacerbating mitochondrial dysfunction and nuclear DNA damage. This work provides an effective method for increasing drug sensitivity based on telomerase location in cancer cells.