A multi-functional 3D-printable gel-in-gel system for the delivery of probiotics to the intestine

Bacterial encapsulation has been successfully utilized to either protect probiotics from the harsh gastrointestinal (GI) environment or to provide them with mucoadhesive properties, thereby enhancing their health benefits. However, it is challenging to balance multiple functions within one system, especially when facing the spatially changing environment of the GI tract. Here, we develop a gel-in-gel system with self-adjusting properties for the delivery of probiotics to the intestine. By employing a simple mixing step, mucoadhesive, probiotic-laden microgels are embedded into a protective ‘macro-gel’, i.e., a gelatin matrix enriched with CaCO₃ crystals. This macrogel provides high bacterial survival rates in acidic environments while ensuring a temperature-responsive liberation of the microgels as they travel to the intestine. In vitro and ex vivo experiments demonstrate the high mucoadhesion and stability of the microgels as required for prolonged intestinal retention. The gel-in-gel system not only offers a strategy to encapsulate probiotics in a simple yet multifunctional platform but can also be 3D-printed into chewable shapes for the development of personalized, next-generation oral medicine.