Active targeting and cytosolic delivery of therapeutic payloads are challenging in small extracellular vesicle-based drug delivery systems. Here, the authors engineer fusogen and targeting moiety co-functionalized cell-derived nanovesicles, which can selectively bind to target cells and efficiently fulfill cytosolic delivery through membrane fusion.
. In brief, the existing engineered EVs did not fully demonstrate the capability of cancer-targeting cytosolic drug delivery. The membrane fusion efficiency was also modest. These shortcomings, on the contrary, reflect the strengths of our eFT-CNVs. One more point to emphasize is that the mechanical extrusion of donor cells can generate a large number of nanovesicles in only a few minutes, and the average batch-to-batch variation can be well controlled with optimal manufacturing parameters.
Our study demonstrated that drug-loaded nanovesicles achieved enhanced treatment efficacy compared to free medications. Moreover, compared to nanovesicles without targeting moieties or fusogens, eFT-CNVs can further improve treatment efficacy by delivering drugs to cytosol directly. The effect was particularly obvious in the delivery of gelonin. Gelonin lacks carbohydrate-binding domains, and thus it cannot penetrate cell plasma membranes, making it ineffective in cell treatments.
In addition to drug delivery, the developed eFT-CNVs could be used in cell editing and vaccine applications. For example, conferring specific neoantigens to immune cold tumor cell surface could transform them into immune hot ones, encouraging immune cell-mediated tumor killing. The targeted cytosolic delivery of CRISPR/Cas9 complex with eFT-CNVs would enable specific and efficient gene editing.
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