The microbiota-drug delivery nexus: from pharmacomicrobiomics to live biotherapeutic delivery

The human microbiota, being the diverse communities of bacteria, archaea, fungi, and viruses colonising the gut, skin, respiratory tract, and urogenital system is now recognised as a critical, yet frequently overlooked, determinant of pharmaceutical outcomes. The emerging field of pharmacomicrobiomics has established that microbiota compositional and functional variation profoundly influences drug absorption, distribution, metabolism, and toxicity, whilst drugs reciprocally reshape microbial community structure. However, a fundamental dimension of this relationship has received insufficient attention: the drug delivery system itself is not a passive vehicle but an active participant in microbiota-drug interactions. The physicochemical properties of delivery vehicles, the excipients they contain, and the pharmacokinetic profiles they impose each alter the nature, site, and duration of drug-microbe contact in ways that have significant consequences for therapeutic outcomes. Conversely, the microbiota modulates the performance of drug delivery systems through degrading carriers, altering mucosal permeability, and modifying the environment in which release occurs. Beyond these bidirectional interactions, controlled release technology offers a distinct and compelling opportunity, including the deliberate exploitation of microbial metabolic activity as a trigger for site-specific drug release and the delivery of the microbiota itself. This review introduces the concept of the microbiota-drug delivery nexus, providing the first comprehensive account of the bidirectional interactions between drug delivery systems and the human microbiota, with a specific focus on how oral and non-oral delivery vehicles interact with the gut microbiota. Critical knowledge gaps are identified, which highlight emerging opportunities for microbiota-informed formulation design, and make the case that incorporating microbiota considerations into drug delivery science is no longer optional but essential for the rational development of next-generation therapeutics.