Engineered bacterial extracellular vesicles for osteoporosis therapy

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.

Nanoparticle-based therapeutic, prevention, and detection modalities have the potential to greatly impact how diseases are diagnosed and managed in the clinic. With the wide range of different nanomaterials available to nanomedicine researchers, the rational design of nanocarriers on an application-specific basis has become increasingly commonplace. In this review, we provide a comprehensive overview on an emerging platform: cell membrane coating nanotechnology. As one of the most fundamental units in biology, a cell carries out a wide range of functions, including its remarkable ability to interface and interact with its surrounding environment. Instead of attempting to replicate such functions via synthetic techniques, researchers are now directly leveraging naturally derived cell membranes as a means of bestowing nanoparticles with enhanced biointerfacing capabilities. This top-down technique is facile, highly generalizable, and has the potential to greatly augment the potency and safety of existing nanocarriers. Further, the introduction of a natural membrane substrate onto the surface of a nanoparticle has enabled additional applications beyond those already associated with the field of nanomedicine. Despite the relative youth of the cell membrane coating technique, there exists an impressive body of literature on the topic, which will be covered in detail in this review. Overall, there is still significant room for development, as researchers continue to refine existing workflows while finding new and exciting applications that can take advantage of this emerging technology. Cell membrane coating is an emerging nanotechnology. By cloaking nanomaterials in a layer of natural cell membrane, which can be derived from a variety of cell types, it is possible to fabricate nanoplatforms with enhanced surface functionality. This can lead to increased nanoparticle performance in complex biological environments, which can benefit applications like drug delivery, imaging, phototherapies, immunotherapies, and detoxification.