Morphology-directed radiosensitization of MoSe2 nanoplatforms for promoting cervical cancer radiotherapy

Radioresistance has been the main obstacle of cervical cancer radiotherapy. Hence, it’s urgent need to develop effective radiosensitizers for improving the radiotherapeutic efficacy. MoSe2 has been recognized as a promising therapeutic nanoplatform in radio/photo-mediated cancer therapy, due to its narrow bandgap and good photoelectric/photothermal conversion capabilities, while these physical properties and its biological performance can be various depending on its structure. Herein, radiosensitization nanosystems based on two common forms of MoSe2 nanomaterial, 2D nanosheet (NS) and 3D nanoflower (NF), were developed, and their therapeutic efficacy and mechanisms in treating cervical cancer were contrastively analyzed. In vitro experiments on Hela and Siha cells demonstrated superior synergistic therapeutic efficacy of MoSe2 NF-RGD over MoSe2 NS-RGD. Further analysis revealed that compared to MoSe2 NS-RGD, MoSe2 NF-RGD efficiently targeted and accumulated in cancer cell mitochondria, leading to mitochondria-mediated apoptosis associated with p53 phosphorylation. Moreover, the metabolites of MoSe2 NF-RGD including selenocystine (SeCys2) and methylselenocysteine (MeSeCys2) also contributed to its unique advantages in radiosensitized cancer-killing effect. Consistently, in vivo study confirmed higher therapeutic efficacies of MoSe2 NF-RGD combined with X-ray against the primary tumor as well as distant tumor through boosting the infiltration of some specific immune cells including dendritic cells (DCs) and NK1.1 cells. Collectively, this work revealed the influence of material structure on the biological performance and radiotherapeutic efficacy of MoSe2-based nanosystems and the underlying mechanisms for these structure-dependent difference.