Nanosensitizer for enhanced radiotherapy via tumor microenvironment reshaping and ROS amplification

<b>Rationale:</b> Radiotherapy is a principal modality in cancer treatment, effectively controlling local tumor growth and possessing the potential to enhance the immunogenicity of tumor cells, thereby improving the antitumor immunity. However, its efficacy is often limited by insufficient production of reactive oxygen species (ROS), tumor hypoxia, and the immunosuppressive tumor microenvironment (TME). Therefore, developing strategies to amplify ROS and reshaping the hypoxic, immunosuppressive TME is crucial for advancing radiotherapy. <b>Methods:</b> In this study, we designed a polyethylene glycol (PEG)-modified gold@manganese dioxide core-shell nanoparticle (GMCN@PEG) that is responsive to the acidic TME. We then investigated its ability to enhance radiotherapy and magnetic resonance-computed tomography (MR-CT) dual-modality imaging both <i>in vivo</i> and <i>in vitro</i>. <b>Results:</b> GMCN@PEG exhibits good biocompatibility under neutral physiological conditions and, upon exposure to the acidic TME, it alleviates tumor hypoxia and amplifies ROS production. This leads to enhanced radiotherapy sensitivity and the induction of immunogenic cell death (ICD). Furthermore, GMCN@PEG activates the cGAS-STING signaling pathway, promoting dendritic cells (DCs) maturation, macrophages M1 polarization, and T cells infiltration, effectively counteracting the immunosuppressive state within the TME. Additionally, GMCN@PEG enhances dual-modality imaging through MR-CT, achieving the integration of diagnosis and therapy. <b>Conclusion:</b> In summary, GMCN@PEG as a multifunctional nanosensitizer, demonstrate significant potential and promise in improving the efficacy of radiotherapy, reshaping the tumor microenvironment, promoting antitumor immunity, and biomedical imaging enhancement.