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-Nys) for preferential delivery. Compared with M1-derived exosomes, CCR2(+)-Fe-M1-Nys 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-Nys 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 repolarization thereby provoke tumor-specific immune response. Such nano-Fenton reactor as well as M2 nanorepolarizer are proved cooperatively efficient in already formed lung metastasis mice model and shed lights on the exploration of synergistic strategies for cancer metastasis management.

Automated summary

Ferroptosis has shown effectiveness in cancer metastasis treatment, but limitations in internal ferric aggregation and catalysis at desired sites hinder further therapeutic applications. Modified M1 macrophages with up-regulated CCR2 expression serve as Fe3O4 nanoparticles carrier, which are extruded into exosome-mimic nanovesicles for preferential delivery. This approach demonstrates promising modification efficiency and large-scale production, with potential for inducing macrophage repolarization and tumor-specific immune response in cancer metastasis management.