Engineering of an intelligent cascade nanoreactor for sequential improvement of microenvironment and enhanced tumor phototherapy

Abstract Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a new tumor treatment method with high specificity, low toxicity and non-invasive advantages. Herein, we synthesized hyaluronic acid (HA) modified mesoporous Prussian blue (PB) nanoparticles (HA-PB NPs) with macrophage transformation (pro-tumor M2 to anti-tumor M1) and self-produced oxygen (O2) properties. After that, the photosensitizer indocyanine green (ICG) was loaded, to realize PTT and PDT synergistic treatment of 4T1 tumor under a single near-infrared (NIR) laser irradiation. In vitro experiments showed that HA-PB can improve the stability of ICG. Drug release experiment proved the acidic tumor microenvironment containing rich hyaluronidase (HAase) could achieve local and specific drug release in targeted tumor tissue. HA-PB can be internalized by 4T1 cells and M2 macrophages. After M2 phenotype being reversed into M1 macrophages, H2O2 secreted by M1 can be catalyzed by HA-PB nanozyme to generate O2 for tumor microenvironment improvement and O2 self-supplied PDT. With co-culture of M2 macrophages and 4T1 cells, HA-PB/ICG could effectively induce DNA breakage (37.9 ± 3.2%) and tumor cell apoptosis. In vivo results indicated that HA-PB/ICG can enhance the accumulation capacity and retention time of ICG at the tumor site. Under 808 nm laser irradiation, the temperature and ROS level of tumor site in HA-PB/ICG group raised 22.7 °C and 32 folds, respectively, showing superior photothermal and ROS conversion abilities. Furthermore, pharmacodynamic results proved that HA-PB/ICG nanoplatform can significantly inhibit 4T1 tumor proliferation with V/V0 of 0.31 ± 0.16, by precise and synchronous PTT and O2 self-supplied PDT.