A versatile metal–organic nanoplatform in combination with CXCR4 antagonist and PD-L1 inhibitor for multimodal synergistic cancer therapy and MRI-guided tumor imaging

Currently, multimodal synergistic nanoplatform emerges as an important cancer therapy paradigm, however, multimodal synergistic theranostic nanoplatform remains to be developed. Herein, using the mouse model of breast cancer, a versatile multimodal synergistic theranostic nanoplatform is rationally designed and synthesized for enhancing chemodynamic therapy (CDT), overcoming immunosuppression within tumor microenvironment, and inhibiting metastasis as well as tracking tumor. To fulfill our design, a composite Fe/Mn magnetic nanoparticle is first synthesized by loading with Fe3O4 and BMS-202 (PD-L1 inhibitor) within a poly(lactide-co-glycolide)-based nanoparticle core, which are further modified with in situ synthesis of MnO2 layer. Then, the composite metal-organic nanoparticle is coated with two targeting moieties hyaluronic acid (HA) and AMD3100 (CXCR4 antagonist), respectively, to achieve the multimodal synergistic theranostic nanoplatform ([email protected]+AMD). With surface targeting modification, [email protected]+AMD exhibits enhanced tumor accumulation, where it effectively consumes endogenous glutathione to generate Mn2+ allowing for the enhanced CDT effect, alleviates tumor hypoxia by O2 generation and reverses the tumor immunosuppression. [email protected]+AMD blocks CXCR4 receptor on cancer cells, thus suppressing the CXCR4-mediated cancer metastasis and invasion. Additionally, [email protected]+AMD would synchronously be achieving tumor tracking by T1-T2 dual-mode magnetic resonance imaging. Collectively, this strategy holds a novel multimodal synergistic theranostics for effective cancer management.