Engineered live bacteria for liver diseases and gut-liver axis disorders: from genetic modification to advanced delivery systems.

Liver diseases, including hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD), impose a significant global health burden, with over 2 million deaths annually and substantial economic losses. Current treatments, primarily pharmacological, face challenges such as insufficient efficacy, poor absorption, and drug resistance. The liver-gut axis, a critical pathway linking the liver and intestines, offers a therapeutic target for these diseases. Engineered live bacteria, modified through genetic engineering and synthetic biology, have emerged as a promising alternative. These bacteria can be designed to deliver therapeutic agents directly to the liver or gut, enhancing efficacy and reducing systemic side effects. This review explores the application of engineered live bacteria in treating liver diseases, focusing on strains such as Bifidobacterium, Escherichia coli Nissle 1917 (EcN), Bacillus subtilis (B. subtilis), Saccharomyces boulardii (S. boulardii), and Lactobacillus reuteri (L. reuteri). It also pays attention to the internal genetic modification and external covalent connection of the original live bacteria. We discuss the design of dosage forms, including capsule formulations, microencapsulation, and nanopreparations, and administration methods like oral and in situ injection. Additionally, we address the challenges and future prospects of using engineered live bacteria to target liver diseases and related conditions, aiming to advance their clinical application and reduce the global burden of liver diseases.