Repurposing the bacterial surface display technology for drug delivery

Bacteria have emerged as versatile platforms for therapeutic delivery, owing to their inherent adaptability, genetic tractability, and ability to interface with the human microbiome and immune system. This review explores the evolution of bacterial engineering for medical applications, emphasizing drug delivery strategies enabled by bacterial surface display technologies. We outline the advantages of surface display—such as enhanced localization, prolonged therapeutic activity, and reduced systemic toxicity—over conventional bacterial secretion and lysis-based delivery methods. The review details key biological mechanisms of surface display in both Gram-negative and Gram-positive bacteria, including outer membrane proteins, sortase-mediated anchoring, and spore-based systems. We also highlight emerging applications of surface-displayed cytokines, nanobodies, and immunomodulatory proteins in cancer therapy, vaccine development, microbiome engineering, and animal health. Innovative approaches combining bacterial display with conjugation systems and biosensors expand the potential of these living therapeutics for precise, responsive, and programmable interventions. Furthermore, we propose a future roadmap that leverages computational tools such as AlphaFold and in silico screening to rationally identify optimal outer membrane anchors, accelerating the design of next-generation surface display platforms. While challenges remain—including regulatory hurdles and microbial stability—continued interdisciplinary innovation with synthetic biology promises to transform engineered bacteria into clinically viable therapeutic agents. This review positions bacterial surface display as a powerful and underexplored modality for targeted drug delivery, bridging synthetic biology, immune engineering, and translational medicine.