From bench to bowel: translating targeted drug delivery through gastrointestinal barriers

The complex and heterogeneous physiological barriers of the gastrointestinal (GI) tract severely limit the efficacy of therapeutic agents for local diseases. This review comprehensively examines strategies for translating targeted drug delivery "from bench to bowel" within the GI tract. We detail the unique biological barriers across GI segments (oral cavity, esophagus, stomach, small intestine, colon) and analyze core challenges in designing effective delivery systems: payload stability, precise targeting/retention, controlled release, mucosal/epithelial penetration, and biocompatibility. The article critically evaluates recent advancements in key delivery platforms, including nanocarriers (liposomes, polymeric NPs, dendrimers, inorganic NPs), hydrogels, and microscale systems (microspheres, microneedles, microrobots), categorizing them by their targeting mechanisms: passive (e.g., the classical EPR effect in solid tumors and EPR-like permeability/retention phenomena in inflamed GI lesions), passive (e.g., EPR effect), active (ligand-mediated), and stimuli-responsive (pH, enzymes, redox, etc.). Furthermore, we highlight the transformative applications of these targeted systems in treating major GI diseases such as inflammatory bowel disease (IBD), GI cancers, and peptic ulcer disease, emphasizing their potential to enhance local efficacy while minimizing systemic toxicity. This work bridges fundamental principles with translational progress to provide a roadmap for developing clinically viable targeted therapies for GI diseases.