Oral Multidrug Co‐Delivery System Targeting Differential Sites for Diabetes Mellitus Treatment

Abstract Although regulation of the blood glucose level is a common therapy for Type 2 diabetes mellitus (T2DM), the root cause of this disease (such as the damage of pancreatic β cells) cannot be solved. Remodeling the pancreatic microenvironment and gut microbial homeostasis to improve β cells dysfunction become a potential strategy but remains challenging. Herein, a curcumin (CUR) and bifidobacterial (BI) co‐delivery system based on the self‐emulsifying technology (CUR‐BI‐SEDDS), which can generate a protective and self‐assembled coating on BI surface to achieve the above strategy is designed. CUR‐loaded oil phase coating endows BI with resistance against gastric invasion and helps BI colonize to positively regulate the abundance of gut microbiota. Following oral ingestion, the CUR‐loaded oil phase is self‐emulsified into nano‐emulsion, separated from BI, and delivers CUR to pancreas via the chylomicron pathway to remodel the inflammatory pancreatic microenvironment. As a result, CUR‐BI‐SEDDS showed excellent efficacy in restoring the islet β cell function, thus maintaining the systemic glucose homeostasis via only once administration every day. This study not only provides a promising regimen for thorough T2DM therapy but also explores a versatile oral co‐delivery platform for combination of chemo‐drugs and living biotherapeutics, which can exert potency at diverse target sites.