Biohybrid nanosystems are at the center of personalized medicine, affording prolonged circulation time and targeting to the disease site, and serving as antigenic sources of vaccines. The optimization and functionality parameters of these nanosystems vary depending on the properties of the core particles. In this work, the effects of the core particles’ surface charge and hydrophobicity are evaluated on the nanosystem coating with vesicles derived from plasma membrane. The measured parameters are the dimensions, surface charge, shape, and stability of the biohybrid nanosystems, both in buffer and in biologically relevant media (plasma and simulated synovial fluid). Moreover, the cytocompatibility properties of the developed nanosystems are evaluated in different cell lines mimicking the target cell
populations and other districts of the body involved in the distribution and elimination of the nanoparticles. Finally, the immunological profile of the particles is investigated, highlighting the absence of immune activation promoted by the nanoplatforms.