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Extracellular vesicle-hitchhiking nanoliposomes for cancer-associated fibroblast phenotype modulation impede
Fang Chen1, Zhidi He1, Rong Guo2
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan Med-X Center for Materials, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China.
Abstract:
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.
Insights
This study introduces an extracellular vesicle (Ev)-hitchhiking strategy to target cancer-associated fibroblasts (CAFs) at distant metastatic sites. This approach effectively delivers drugs to remodel the tumor microenvironment and suppress cancer metastasis.
Area of Science:
- Oncology
- Nanotechnology
- Cell Biology
Background:
- Metastasis is a critical cancer progression stage.
- Cancer-associated fibroblasts (CAFs) promote metastasis.
- Targeting CAFs in distant metastasis is challenging due to their heterogeneity and delivery hurdles.
Purpose of the Study:
- To develop an effective strategy for targeting CAFs in distant metastatic sites.
- To leverage tumor extracellular vesicles (Evs) for targeted drug delivery.
- To investigate the therapeutic potential of an Ev-hitchhiking nanoliposome system loaded with ATRA and lenvatinib for cancer metastasis.
Main Methods:
- Developed a labeling strategy for tumors and tumor-derived Evs.
- Engineered modified nanoliposomes to hitchhike on labeled Evs.
- Utilized the Ev-hitchhiking nanoliposomes loaded with ATRA and lenvatinib.
- Evaluated the impact on CAF characteristics, metastatic microenvironment, and tumor growth/metastasis.
Main Results:
- Nanoliposomes concentrated in CAFs at distant metastatic sites by hitchhiking on labeled Evs.
- The Ev-hitchhiking strategy successfully targeted labeled tumors.
- Loaded drugs (ATRA and lenvatinib) regulated CAF myogenic and inflammatory traits.
- The metastatic microenvironment was remodeled, suppressing tumor growth and metastasis.
Conclusions:
- The Ev-hitchhiking approach offers a promising strategy for enhancing tumor elimination.
- This method can modulate CAFs and other Ev-activated cells in distant metastasis.
- The developed system represents a potential breakthrough in cancer therapy.
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