Microbiome-active drug delivery systems (MADDS): Leveraging microbial stimuli for controlled drug release

Abstract

The human microbiome comprises diverse microbial communities that inhabit tissues and biofluids throughout the body, including the gastrointestinal tract, lungs, vagina, and skin. These sites create dynamic microenvironments rich in enzymes, metabolites, and chemical gradients that act both as biological barriers and as localised targets for drug delivery. This review provides an overview of Microbiome-Active Drug Delivery Systems (MADDS), an emerging class of platforms that exploit microbial stimuli for site-specific therapeutic release. Unlike conventional systems that simply coexist with the microbiome, MADDS harness resident microbes and their metabolites to trigger drug activation, retention, or release. This enables spatially precise delivery of small molecules, biologics, and live biotherapeutic products (LBPs). Key strategies include enzyme-, environment-, metabolite-, biofilm-, and receptor-responsive designs, each tailored to microbial niches and applied across infectious, inflammatory, and metabolic disorders. However, challenges remain, including microbiome variability between individuals, regulatory uncertainty around hybrid biologic-material systems, and the need for scalable GMP-compliant manufacturing. This review therefore outlines the current approaches for engineering MADDS and the future steps required for clinical translation. By exploiting microbial cues for controlled drug release, MADDS offer a practical route to more targeted and patient-specific therapies.