Background: intrahepatic islet transplantation in patients with T1D is limited by donor availability and lack of engraftment. To overcome these limitations, based on our experience with decellularized rat lung as scaffold for the generation of Vascularized Islet Organ (VIO, lung scaffold repopulated by murine islets and HUVEC cells), we engineered an upgrade based on human blood-derived endothelial cells (BOECs - Blood Outgrowing Endothelial Cells) and immature neonatal porcine islet clusters (NPIs). Methods: NPIs and BOECs phenotype profile was assessed by flow cytometry, insulin secretion test and tube formation assay. Rat lung was decellularized with SDS and Triton and seeded with NPIs and BOECs, generating a Vascularized Endocrine Pancreas (VEP). VEP was cultured for 7 days in a customized bioreactor specifically designed to allow cell integration. The β cell death in mature VEPs was estimated during ex vivo organ maturation evaluating miR-375 expression ddPCR compared to batch matched NPIs in standard condition. Matured VEPs and control NPIs function were measured by dynamic glucose perifusion and insulin quantification (by ELISA/IF). Thus, VEPs were subcutaneously transplanted in diabetic immunodeficient NSG recipients and compared with matched NPIs transplanted in different implantation sites: kidney capsule (KC-NPIs), deviceless (DL-NPIs) and liver (LV-NPIs). Results: Matured VEPs showed a regenerated vascular network (CD31+) with NPIs (insulin+) integrated. miR-375 was expressed in NPIs but not in BOECs, as expected. VEP was able to significantly reduce β cell death (p<0.05). Matured VEPs were able to sustain NPIs engraftment, survival and significantly improve insulin secretion during the maturation process compared to batch matched NPIs cultured in standard conditions (AUC VEPs first phase: 3.765±0.90; NIPs 1.60±0.25 p<0.01). In long-term transplants in diabetic mice, VEPs demonstrated a significant NPIs engraftment with a prompt function after implantation and the reversal of the glycaemia within 2 days until 60 days after implantation, showing significant superior function compared to all the internal controls (KC-NPIs, DL-and LV-NPIs). Conclusions: VEP technology is able not only to foster the NPIs functional endocrine maturation in vitro but also to immediately perform in vivo upon transplantation for over 2 months, compared to normal performance within 8 weeks after implantation in different state of the art preclinical models. Given recent progress in genetic engineering of NPI donor pigs, this technology may enable assembly of immune-protected functional personalized endocrine organs. VEP is the first organ to our knowledge assembled with relevant source of endocrine and endothelial cells suitable for future clinical translation.