Dual-Targeting Chitosan Nanogels Enable Magnetic Resonance Imaging-Guided Synergistic Chemo/Chemodynamic Therapy against Prostate Cancer Bone Metastasis

Abstract Prostate cancer bone metastasis is a major therapeutic challenge due to poor drug selectivity and insufficient tumor targeting. Herein, we engineer a biomimetic dual bone/tumor-targeting chitosan nanogel (NG) platform (UCNG/ZOL@CM) cloaked with homologous cancer cell membranes (CM) for co-delivery of ultrasmall iron oxide nanoparticles (USIO NPs) and zoledronic acid (ZOL), enabling T1-weighted magnetic resonance (MR) imaging-guided synergistic chemo/chemodynamic therapy. The developed UCNG/ZOL@CM with an average diameter of 211.3 nm displays good colloidal stability and a pH-responsive drug release profile. Benefiting from ZOL’s bone affinity and CM-mediated homologous targeting, the platform preferentially accumulates at bone metastatic lesions. Under the acidic metastatic microenvironment, the NGs dissociate to release ZOL and USIO NPs, suppressing the mevalonate pathway while inducing Fenton/Fenton-like oxidative stress, leading to glutathione depletion, lipid peroxidation, and ferroptosis/apoptosis of cancer cells. Concurrently, acid-triggered USIO exposure enhances T1 relaxivity for improved MR imaging. In a prostate cancer bone metastasis mouse model, the UCNG/ZOL@CM enables efficient MR imaging of metastatic foci, markedly inhibits primary tumor growth and pulmonary metastasis, prolongs survival, and alleviates tumor-associated osteolysis. The developed biomimetic NG platform offers a promising theranostic strategy for precision management of prostate cancer bone metastasis.