Regulating Bacteria-Host Interactions for Disease Intervention by Covalent Conjugation of Bacterial Surface

The interactions between bacteria and in vivo environments are critical for microorganism-host association, which plays essential roles in host immunomodulation and nutrient metabolism. Regulating the interactions of bacteria with various in vivo interfaces can vary microorganism-host relationships, offering a promising approach to intervene immune and/or metabolism disorders. However, the rationale behind the modulation of bacterial interactions with surroundings is poorly understood and methods capable of modifying bacteria to tune the crosstalk with the host have been rarely reported. Recently, considerable attention has been paid to bacterial surface modification, where bacteria can be incorporated with diverse exogenous components. Among different modification strategies, surface conjugation based on covalent chemical linkages has emerged as a key tool to design and introduce functional motifs. Particularly, surface covalent conjugation (SCC) allows for stable attachment of active components to specific sites on bacteria with molecular-level specificity and selectivity, providing a solid foundation for precisely regulating bacterial interactions with in vivo environments.In this Account, we summarize the recent advancements achieved by our research team in regulating the interactions of bacteria with in vivo interfaces at both cellular and tissue levels via covalent conjugation of bacterial surface, aiming to develop alternative insights for disease intervention. First, we utilize the abundant reaction sites on bacterial surface to develop flexible yet versatile covalent modification strategies that do not compromise bacterial viability. Using reactive group-mediated covalent conjugation, such as acylation of amino groups, amidation of carboxyl groups, thiol-Michael addition, or in situ dopamine polymerization, small molecules, macromolecules, and nanoparticles with various functions can be attached onto bacteria. Next, we outline how SCC endows bacteria with additional functions, by combining the inherent properties of bacteria with various synthetic functional payloads. For instance, covalent attachment with specific ligands can strengthen the recognition and binding of bacteria with targeting cells, thereby resulting in enhanced accumulation of bacteria at lesion sites. Moreover, covalent incorporation of components with strong permeability or adhesion properties is able to improve bacterial colonization at tissue surfaces of interest. In addition, functional components with tunable physicochemical properties can be conjugated onto bacteria to remodel the redox microenvironments of lesion sites. Then, we show the benefits of specific interactions of modified bacteria with in vivo environments, including those between bacteria and cells, bacteria and tissues, as well as bacteria and disease microenvironments. We also highlight the importance of regulating bacteria-host interactions in disease intervention, particularly the alleviation of inflammatory bowel disease through oral ingestion, the treatment of tumors via intravenous injection, and the healing of infected wounds by topical administration. Lastly, we discuss the prospects and challenges of using SCC to modify bacteria in terms of regulating bacterial interactions with in vivo environments, especially the potential of translating these modified bacteria from laboratory to clinical practice. We anticipate that the strategy of SCC, along with manipulable interactions between modified bacteria and cell/tissue surfaces proposed in this Account, will promote the development of bacterial engineering methodologies and inspire innovative strategies to modify microorganism-host interface for disease intervention.