Engineering a Dual-Function Starch–Cellulose Composite for Colon-Targeted Probiotic Delivery and Synergistic Gut Microbiota Regulation in Type 2 Diabetes Therapeutics

<b>Objectives:</b> This study engineered a colon-targeted drug delivery system (CTDS) using the dual pharmaceutical and edible properties of <i>Pueraria lobata</i> to encapsulate <i>Lactobacillus paracasei</i> for Type 2 diabetes mellitus (T2DM) therapy. <b>Methods:</b> The CTDS was designed as a core-shell composite through microwave-hydrothermal engineering, comprising the following: (1) a retrograded starch shell with acid/enzyme-resistant crystallinity to protect probiotics from gastric degradation; (2) a porous cellulose core derived from <i>Pueraria lobata</i>'s natural microstructure, serving as a colonization scaffold for probiotics. <b>Results:</b> Structural characterization confirmed the shell's resistance to acidic/pancreatic conditions and the core's hierarchical porosity for bacterial encapsulation. pH/enzyme-responsive release kinetics were validated via fluorescence imaging, demonstrating targeted probiotic delivery to the colon with minimal gastric leakage. In diabetic models, the CTDS significantly reduced fasting blood glucose and improved dyslipidemia, while histopathological analysis revealed restored hepatic and pancreatic tissue architecture. Pharmacologically, the system acted as both a probiotic delivery vehicle and a microbiota modulator, selectively enriching <i>Allobaculum</i> and other short-chain fatty acid (SCFA)-producing bacteria to enhance SCFA biosynthesis and metabolic homeostasis. The CTDS further exhibited direct compression compatibility, enabling its translation into scalable oral dosage forms (e.g., tablets). <b>Conclusions:</b> By integrating natural material engineering, microbiota-targeted delivery, and tissue repair, this platform bridges the gap between pharmaceutical-grade probiotic protection and metabolic intervention in T2DM.