# Steering the Clinical Translation of Delivery Systems for Drugs and Health Products
## 3 Poster Presentations
### GMP-Compliant Freeze-Dried Extracellular Vesicles: Regenerative and Nano-Drug Delivery Systems  
[PERSON] *, [PERSON] and [PERSON]  
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy  
* Correspondence: [EMAIL_ADDRESS]  
Mesenchymal Stem Cells (MSCs)-secretome is composed of soluble factors (proteins, growth factors, and cytokines) and extracellular vesicles (EVs) that can be divided into microvesicles and exosomes. MSC-secretome represents a valid therapeutic approach in place of parental cells for the treatment of chronic and acute diseases [45]. Despite the great interest addressed to the MSC-secretome, missing steps are required for the secretome \"pharmaceuticalization\" to obtain a high quality, safe and effective medicinal product, as well as for the optimal formulation development.  
Important requirements for the development of a medicinal product are: To obtain a scalable and GMP-compliant production process and the stability and the shelf-life of the final product; ultrafiltration, as purifying process, and freeze-drying fit with this requirement. We combined these two techniques obtaining a ready-to-use powder named lyo-secretome [46; 47]. EV integrity and morphology were not affected by the technological processes; product resulted as no cytotoxic and no hemolytic confirming its safety profile. Efficacy of lyo-secretome was proven against oxidative stress-induced damages [2], as immunomodadulant agent [47] and in a wound healing murine model. Furthermore, proteomic characterization of lyo-secretome revealed that it contains alpha1-antitrypsin (AAT) with in vitro anti-elastase activity, paving the way for the use in lung degeneration AAT deficiency [48].  
All this evidence demonstrated that lyo-secretome could be considered to be a new active pharmaceutical ingredient (API). Furthermore, the nano-size and the membrane structure of EVs make them ideal candidates as nano-drug delivery systems (DDS); EVs resulted as similar to liposomes but, at the same time, presented high stability in bloodstream and low immunogenicity with respect the synthetic nanosystems. MSC-EVs maintained the homing ability to injured site of their parental cells; this characteristic makes MSC-EVs suitable smart DDS to avoid off side effects, and enhance the specific uptake by target cells. In this context, we proposed the combined use of silk fibroin nanoparticles, as technological carrier, and EVs, as biological carrier, to obtain a drug delivery system named \"carrier in carrier\". The nanoparticles can efficiently incorporate hydrophobic and/or hydrophilic drugs, while the EVs could assure an adequate drug targeting due to their innate ability to reach the damaged tissues.  
This combined biological-technological approach could represent a novel class of nanosystems, combining beneficial effects of both regenerative cell therapies and pharmaceutical nanomedicine, avoiding the use of viable replicating stem cells [49]. This evidence demonstrates that MSC-secretome can be used both as API and DDS; although human and veterinary clinical trials are still few, we are confident that many will start in the nearly future.  
This work was supported by Interreg V-A Italy-Switzerland 2014-2020-ATEx-Advanced Therapies Experiences. Project ID 637541.