The nanostructured secretome.

The term secretome, which traditionally strictly refers to single proteins, should be expanded to also include the great variety of nanoparticles secreted by cells (secNPs) into the extracellular space, which ranges from high-density lipoproteins of a few nanometers to extracellular vesicles and fat globules of hundreds of nanometers. Widening the definition is urged by the ever-increasing understanding of the role of secNPs as regulators/mediators of key physiological and pathological processes, which also puts them in the running as breakthrough cell-free therapeutics and diagnostics. "Made by cells for cells", secNPs are envisioned as a sweeping paradigm shift in nanomedicine, promising to overcome the limitations of synthetic nanoparticles by unsurpassed circulation and targeting abilities, precision and sustainability. From a longer/wider perspective, advanced manipulation would possibly make secNPs available as building blocks for future "biogenic" nanotechnology. However, the current knowledge is fragmented and sectorial (the majority of the studies being focused on a specific biological and/or medical aspect of a given secNP class or subclass), the understanding of the nanoscale and interfacial properties is limited and the development of bioprocesses and regulatory initiatives is in the early days. We believe that new multidisciplinary competencies and synergistic efforts need to be attracted and augmented to move forward. This review will contribute to the effort by attempting for the first time to rationally gather and elaborate secNPs and their traits into a unique concise framework - from biogenesis to colloidal properties, engineering and clinical translation - disclosing the overall view and easing comparative analysis and future exploitation.