Stimuli-Responsive Nanocoatings Enable Controlled Oral Delivery of Therapeutic Bacteria

Oral bacteriotherapy has given rise to an unprecedented potential in treating a variety of diseases, especially gastrointestinal tract-associated immune and metabolic disorders, through reversing microbial imbalance-induced physiological dysfunctions. However, living therapeutic bacteria are often plagued by unsatisfactory treatment outcomes due to their impaired oral viability, unpredictable intestinal distribution, and undesired in vivo colonization. Controlled delivery of therapeutic bacteria via customized vehicles is able to overcome these difficulties by protecting a bacteria from environmental insults, selectively releasing in the intestine, and/or increasing targeted accumulation at the lesion site. Recently, remarkable efforts have been made on cell surface modification to improve the in vivo delivery of therapeutic bacteria based on specific physiological environments and/or pathological features. Among these purposive modification strategies, the formation of a stimuli-responsive nanocoating represents a versatile platform to introduce bacteria with extra functions, such as enhanced resistance, site-specific exposure, and physiological signal-triggered in situ activation in the gastrointestinal tract, offering a promising approach for precisely delivering therapeutic bacteria for advanced oral bacteriotherapy. In this Account, we summarize the recent advances from our group in manipulating bacterial behaviors through the construction of gastrointestinal stimuli-responsive nanocoatings, with the aim to enable controlled oral delivery of living therapeutic bacteria. First, we report the use of available reactive moieties on the bacterial surface to form diverse stimuli-responsive nanocoatings without affecting bacterial viability. By virtue of abundant intermolecular interactions, such as electrostatic attraction, hydrophobic adsorption, π-π stacking, coordination bonding, or heterogeneous nucleation mineralization, nanocoatings consisting of functional small molecules, polymers, and/or nanoparticles can be formed on the bacterial surface. We describe how these nanocoatings can intelligently respond to specific gastrointestinal stimuli, thereby enabling the controlled oral delivery of modified bacteria. For instance, the introduction of a gastric acid-responsive nanocoating can neutralize acidic insult to enhance bacterial tolerance, ensuring the passage of intact bacteria through the stomach. Additionally, an enteric nanocoating can be triggered to dissolve in response to pH fluctuation, consequently rendering a selective release of therapeutic bacteria in the intestine. Moreover, equipping bacteria with a pathological signal-sensitive nanocoating enables the controllable exposure of therapeutic bacteria at the lesion site, achieving targeted delivery to the lesion site. Then, we show the advantages of stimuli-responsive nanocoating-enabled controlled oral delivery of therapeutic bacteria for disease intervention. Specifically, we highlight the applications involving the treatment of intestinal infections, the alleviation of chemically induced ulcerative mucositis, the synergistic treatment of pathogen-induced colitis, and the prevention of gut microbiota disorder-caused atherosclerosis. Lastly, we discuss the prospects and challenges of using stimuli-responsive nanocoatings to manipulate the functions of therapeutic bacteria for controlled oral delivery and corresponding disease management, particularly the translational potential from laboratory research to clinical implementations. We anticipate that these stimuli-responsive nanocoating-based oral delivery systems proposed in this Account, as well as their tunable interplays with the gastrointestinal environments, will advance the development of next-generation living therapeutics and provide innovative strategies for disease intervention.