Journal
ADVANCED SCIENCE
Volume 8, Issue 10, Pages -Publisher
WILEY
DOI: 10.1002/advs.202002787
Keywords
combination therapy; lipids rearrangement; low pH reprogramming; patient‐ derived xenografts; tumor exosomes
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Funding
- Innovative Research Group Project of the National Natural Science Foundation of China [21821005]
- National Natural Science Foundation of China [81871912, 81970530]
- National Key R&D Program of China [2017YFA0207900]
- Chinese Academy of Sciences [XDB29040303]
- Shanghai Municipal Health Bureau Key Disciplines Grant [ZK2019C012]
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Research shows that under low-pH conditions, the uptake efficiency of tumor exosomes increases while retaining cell specificity. A glycerolipid self-aggregation-based mechanism is revealed through lipidomics analysis and molecular simulations to enhance homologous uptake. By using near-infrared irradiation to induce exosome rupture and release chemodrugs, a smart drug delivery platform is developed for enhanced antitumor effects.
As membrane-bound extracellular vesicles, exosomes have targeting ability for specific cell types, and the cellular environment strongly impacts their content and uptake efficiency. Inspired by these natural properties, the impacts of various cellular stress conditions on the uptake efficiency of tumor iterated exosomes are evaluated, and low-pH treatment caused increased uptake efficiency and retained cell-type specificity is found. Lipidomics analyses and molecular dynamics simulations reveal a glycerolipid self-aggregation-based mechanism for the enhanced homologous uptake. Furthermore, these low-pH reprogrammed exosomes are developed into a smart drug delivery platform, which is capable of specifically targeting tumor cells and selectively releasing diverse chemodrugs in response to the exosome rupture by the near-infrared irradiance-triggered burst of reactive oxygen species. This platform exerts safe and enhanced antitumor effects demonstrated by multiple model mice experiments. These results open a new avenue to reprogram exosomes for smart drug delivery and potentially personalized therapy against their homologous tumor.
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