Extracellular vesicle–hitchhiking nanoliposomes for cancer-associated fibroblast phenotype modulation impede metastasis progression

Metastasis represents a crucial cancer progression and is promoted by cancer-associated fibroblasts (CAFs). Modulating CAFs in distant metastasis is challenging due to their diverse phenotypes and the lack of effective delivery strategies. Inspired by the tropism of tumor extracellular vesicles (Evs) expressing specific integrins toward fibroblasts, we developed a labeling strategy for both tumors and tumor-derived Evs. Our modified nanoliposomes, by hitchhiking on these labeled Evs, concentrated in CAFs at distant metastatic sites while simultaneously targeting the labeled tumor. This Ev-hitchhiking strategy, in combination with the loaded drugs ATRA and lenvatinib, efficiently regulated the myogenic and inflammatory characteristics of CAFs, remodeled the metastatic microenvironment, and suppressed tumor growth and metastasis. The labeling and Ev-hitchhiking approach holds promise for enhancing tumor elimination and modulating CAFs or other Ev-activated cells in distant metastasis, offering a potential breakthrough in cancer therapy.