Synergistic ferroptosis and macrophage re-polarization using engineering exosome-mimic M1 nanovesicles for cancer metastasis suppression

Ferroptosis has been proved effective in cancer metastasis treatment, while the lack of internal ferric aggregation and sufficient catalysis at desired sites astrict the further therapeutic applications. Herein, M1 macrophages engineered with up-regulated CCR2 expression are employed as Fe3O4 nanoparticles carrier. Modified macrophages are further extruded into exosome-mimic nanovesicles (denoted as CCR2(+)-Fe-M1-Nvs) for preferential delivery. Compared with M1-derived exosomes, CCR2(+)-Fe-M1-Nvs exhibit favorable modification and production efficiency, and can be obtained in large quantity. Moreover, correlative in vivo and in vitro measurements find that CCR2(+)-Fe-M1-Nvs are recruited in the metastatic lesion through CCR2-CCL2 axis which is analogous to mature macrophages. Delivered Fe3O4 nanoparticles and M1-related factors (e.g·H2O2) serve as catalyzer of Fenton Reaction and facilitate ferroptosis in tumor, which collectively induce macrophages re-polarization thereby provoke tumor-specific immune response. Such nano-Fenton reactor as well as M2 nano-repolarizer are proved cooperatively efficient in already formed lung metastasis mice model and shed lights on the exploration of synergistic strategies for cancer metastasis management.