Advanced adhesion and targeting strategies to prolong gut residence time and improve eLBP efficacy in colonic diseases

Abstract

Engineered live biotherapeutic products (eLBPs) are genetically modified microorganisms being explored as a novel treatment modality for gastrointestinal (GI) diseases. The therapeutic potential is driven by their ability to selectively interact with host tissues while maintaining inherent probiotic properties that promote gut health. A key limitation of orally administered eLBPs is their poor competitive fitness against resident gut microbes, which often leads to rapid passage through the GI tract and reduced therapeutic efficacy. This challenge can be addressed by engineering eLBPs to extend their residence time in the gut and enhance the precision of therapeutic delivery at the target site. Targeted adhesion is a prevalent mechanism by which eLBPs achieve increased retention within the GI tract. Various targets in the colon have been used as anchors for non-resident microbes such as mucus, the extracellular matrix, and tumorous tissues. Additionally, a range of strategies have been explored for microbial targeting, including chemical surface modifications, genetically engineered surface display systems, metabolic engineering, and stimuli-responsive approaches. In this review, we provide insights into targets and targeting strategies that have been implemented in eLBP development and highlight the gaps that must be addressed to enhance eLBP efficacy through prolonged gut retention. We discuss the development of novel eLBP strains that target various components within healthy or diseased colon tissues for improved efficacy, particularly for inflammatory bowel disease and colorectal cancer. We conclude by detailing perspectives on eLBP design for clinically viable and effective therapeutics.