Comparison of exosome-mimicking liposomes with conventional liposomes for intracellular delivery of siRNA

Exosomes have been extensively explored as delivery vehicles due to low immunogenicity, efficient cargo delivery, and possibly intrinsic homing capacity. However, therapeutic application of exosomes is hampered by structural complexity and lack of efficient techniques for isolation and drug loading. Liposomes represent one of the most successful therapeutic nanocarriers, but are frequently criticized by short blood circulation and inefficient intracellular drug delivery. In this circumstance, a promising strategy is to facilitate a positive feedback between two fields. Herein, exosome-mimicking liposomes were formulated with DOPC/SM/Chol/DOPS/DOPE (21/17.5/30/14/17.5, mol/mol), and harnessed for delivery of VEGF siRNA to A549 and HUVEC cells. Compared with Lipo 2000 and DOTAP liposomes, exosome-mimicking liposomes exhibited less than four-fold cytotoxicity but higher storage stability and anti-serum aggregation effect. Exosome-mimicking liposomes appeared to enter A549 cells through membrane fusion, caveolae-mediated endocytosis, and macropinocytosis, while enter HUVEC through caveolae-mediated endocytosis, which revealed that the uptake pathway was dependent on cell types. Notably, exosome-mimicking liposomes exhibited significantly higher cellular uptake and silencing efficiency than PC-Chol liposomes (>three-fold), suggesting the unique lipid composition did enhance the intracellular delivery efficiency of exosome-mimicking liposomes to a significantly greater extent. However, it still remained far from satisfactory delivery as compared to cationic Lipo 2000 and DOTAP liposomes, which warranted further improvement in future research. This study may encourage further pursuit of more exosome-mimicking delivery vehicles with higher efficiency and biocompatibility.