DNAsome with self-boosting ROS generation via tumour acidosis for enhanced and targeted chemodynamic cancer therapy

The anticancer efficacy of chemodynamic therapy (CDT) is significantly reduced owing to the mild acidic nature of the tumour microenvironment (TME). Typically, Fenton catalysts require a strong acidic microenvironment for effective radical generation at the tumour site. Hence the development of new strategies to achieve efficient Fenton reactions by increasing the acidity of the TME is highly demanded for the advancement of CDT-based cancer treatment. Herein, we demonstrate that the loading of the pH-regulator tamoxifen (TAM) into a CDT nanoagent (DNA1some) could significantly boost the efficiency of CDT action by increasing the acidity at the TME. The integration of nucleolin specific aptamer DNA (DNA2) onto the surface of DNA1some (DNA1some/TAM/DNA2) permitted the targeted internalization of the nanoformulation selectively into cancer cells, and consequently, a very efficient Fenton reaction was demonstrated inside the cancer cells selectively, which reduced the “off-target” toxicity of the nanoformulation to the surrounding normal cells. Enhanced cytotoxicity was observed for the TAM-loaded DNA1some compared to DNA1some and TAM alone, which was attributed to the very efficient Fenton reaction by DNA1some due to the increase in acidity caused by the release of TAM. Hence, the pH-regulator-loaded CDT-active DNAsome can potentially overcome the intrinsically insufficient acidity of the TME for enabling efficient Fenton reactions.