Homotypic biomimetic nanotheranostics enhance locoregional Cherenkov radiation-induced photodynamic therapy and ferroptosis in early bone metastases

Theranostics for deep-seated and multifocal bone metastases using conventional nanoparticulate strategies face significant challenges due to limited targeting and insufficient spatial controllability within the lesions. Here, we developed a sophisticated nanocarrier (MC@MH) camouflaged with the homologous prostate cancer cell membrane and ferritin-homing peptide (HKN₂₂). Following systemic injection, the biomimetic nanotheranostics preferentially accumulated in bone metastases through a homotypic targeting mechanism. The acidic/H₂O₂-rich microenvironment triggered the degradation of MnO₂ in MC@MH, leading to the release of Mn²⁺ ions that enhance magnetic resonance imaging (MRI) for bone metastases, particularly at early stages. The HKN₂₂ further promoted interactions between MC@MH and intracellular ferritin. Guided by MRI, the separately administrated radionuclide (⁶⁸Ga-PSMA-617) also actively navigated to metastatic tumors. Based on the Cherenkov radiation effect, it served as a light source in the lesions, precisely irradiating the photosensitizer (Chlorin e6) released from MC@MH. The cytotoxic ROS generated from Cherenkov radiation-induced PDT not only destroyed cancer cells but also destructed ferritin to initiate a cascade of ferroptosis. Overall, our strategy facilitated bone remodeling and repair while preserving bone homeostasis, offering a novel avenue for locoregional and precise theranostics against metastatic cancer in vivo.