RNA interference (RNAi) technology has gradually become a cutting-edge technology for treating diseases such as genetic disorders and cancer due to its huge potential in gene expression regulation. However, the efficient delivery and safety of short interfering RNA (siRNA) remain key challenges for its clinical application.

Exosomes, as natural nanoscale extracellular vesicles, have gradually become a research hotspot for optimizing siRNA delivery due to their excellent biocompatibility, stability, long-lasting in vivo circulation time, and precise tissue targeting ability. However, traditional exosome delivery mainly relies on endocytosis, which leads to rapid degradation of RNA molecules in lysosomes, thereby limiting delivery efficiency.

In a study published in Nature Nanotechnology, a research team led by Gan Yong and Yu Miaorong from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, in collaboration with Hu Guoqing' group from Zhejiang University, combining theoretical modeling with experimental studies, revealed the key role of cholesterol in regulating delivery of RNA drugs by exosomes, and the underlying mechanism.

Using a controllable membrane engineering strategy, researchers prepared exosomes with different cholesterol contents, such as milk exosomes, ginger exosomes, and tumor cell-derived exosomes. Using technologies like transmission electron microscopy, they comprehensively characterized the cellular uptake behavior of these exosomes.

The results showed that increasing cholesterol content in the exosome membrane significantly enhanced its interaction with the target cell membrane, promoting exosome entry into the cell through membrane fusion rather than endocytosis, thus bypassing the limitation of lysosomal degradation.

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