Biomimicking Extracellular Vesicles with Fully Artificial Ones: A Rational Design of EV-BIOMIMETICS toward Effective Theranostic Tools in Nanomedicine

[Image: see text] Extracellular Vesicles (EVs) are the protagonists in cell communication and membrane trafficking, being responsible for the delivery of innumerable biomolecules and signaling moieties. At the moment, they are of paramount interest to researchers, as they naturally show incredibly high efficiency and specificity in delivering their cargo. For these reasons, EVs are employed or inspire the development of nanosized therapeutic delivery systems. In this Perspective, we propose an innovative strategy for the rational design of EV-mimicking vesicles (EV-biomimetics) for theranostic scopes. We first report on the current state-of-the-art use of EVs and their byproducts, such as surface-engineered EVs and EV-hybrids, having an artificial cargo (drug molecule, genetic content, nanoparticles, or dye incorporated in their lumen). Thereafter, we report on the new emerging field of EV-mimicking vesicles for theranostic scopes. We introduce an approach to prepare new, fully artificial EV-biomimetics, with particular attention to maintaining the natural reference lipidic composition. We overview those studies investigating natural EV membranes and the possible strategies to identify key proteins involved in site-selective natural homing, typical of EVs, and their cargo transfer to recipient cells. We propose the use also of molecular simulations, in particular of machine learning models, to approach the problem of lipid organization and self-assembly in natural EVs. We also discuss the beneficial feedback that could emerge combining the experimental tests with atomistic and molecular simulations when designing an EV-biomimetics lipid bilayer. The expectations from both research and industrial fields on fully artificial EV-biomimetics, having the same key functions of natural ones plus new diagnostic or therapeutic functions, could be enormous, as they can greatly expand the nanomedicine applications and guarantee on-demand and scalable production, off-the-shelf storage, high reproducibility of morphological and functional properties, and compliance with regulatory standards.