Bacteria, due to their inherent adaptability, genetic modifiability, and the ability to interface with the human microbiome and immune system, have become a multifunctional platform for therapeutic delivery. This review explores the evolution of bacterial engineering in medical applications and emphasizes the drug delivery strategies achieved through surface display techniques. We outline the advantages of surface display, such as enhanced targeting, prolonged therapeutic activity, and reduced systemic toxicity compared to traditional bacterial secretion and lysis-based delivery methods. This review details the key biological mechanisms of surface display in Gram-negative and Gram-positive bacteria, including outer membrane proteins, sorting enzyme-mediated anchoring, and spore-based systems. We also highlight the emerging applications of surface-display cytokines, nanobodies, and immunomodulatory proteins in cancer treatment, vaccine development, microbiome engineering, and animal health. Innovative methods combining bacterial display with linker systems and biosensors expand the potential of these living therapies in precise, responsive, and programmable interventions. Additionally, we propose a future roadmap that utilizes computational tools such as AlphaFold and computer screening to rationally identify the best outer membrane anchors, thereby accelerating the design of the next surface display platform. Despite remaining challenges, including regulatory barriers and microbial stability, the continuous interdisciplinary innovation in synthetic biology is expected to transform engineered bacteria into clinically viable therapeutic agents. This review positions bacterial surface display as a powerful and underexplored targeted drug delivery approach, connecting synthetic biology, immunology engineering, and translational medicine.
This study was published in Advanced Drug Delivery Reviews under the title "Repurposing the bacterial surface display technology for drug delivery". References:
DOI: 10.1016/j.addr.2025.115701