<p>The complexity of inflammatory bowel disease (IBD) and its pharmacological management has driven research to explore novel treatment options for this condition. Among the emerging therapies, Mesenchymal Stromal Cells (MSCs) have proven to be effective, showing strong immunomodulatory properties. However, the efficiency of direct MSC administration has been questioned due to their short half-life and risk of rejection. As an alternative, MSCs secretome, containing the beneficial paracrine effectors of MSCs, is being explored as a promising cell-free therapeutic tool. However, the oral delivery of this secretome is complex and presents a significant technological challenge. Additionally, the personalization of secretome-based therapies is essential, as it is a costly treatment that requires dose customization for each patient. This study introduces a novel approach for the oral delivery of adipose-tissue derived MSC secretome (AT-S) using 3D-printed core-shell tablets. Remarkably, lyophilized secretome (LpAT-S) was used during the study to improve the manageability and stability of the secretome. The 3D printed system proved to be capable of protecting secretome proteins from gastric degradation, offering an unprecedented possibility for the oral administration of secretome therapies. Overall, this study shows that 3D printing offers a promising, patient-friendly solution for the oral administration of MSC secretome for the first time, aligning with precision medicine goals to provide tailored therapies for IBD.</p> Graphical abstract <p></p>