The bidirectional interface between oral drug and the gut microbiome: Implications for drug delivery.

Oral administration remains the preferred route for systemic therapy, yet achieving consistent drug exposure is often hindered by interindividual variability. The gut microbiome is increasingly recognized as a key determinant in this variability, capable of transforming, inactivating, or degrading drugs through microbial enzymatic activity. Conversely, advanced oral delivery systems, comprising polymeric matrices, lipid vesicles, hydrogels, and nanocarriers, can reshape microbial composition and function, either unintentionally or as part of a deliberate formulation strategy. This review examines the bidirectional interactions between oral drug delivery systems and the gut microbiome, emphasizing their implications for drug exposure, therapeutic predictability, and safety. We discuss delivery system-microbe interactions that govern drug stability, transport, and activation, alongside emerging microbiome-responsive formulation designs that leverage microbial cues for site-specific release. Advanced experimental and analytical tools, including gut-on-chip platforms, humanized and gnotobiotic animal models, and integrated pharma-co-microbiomics approaches, are highlighted as enablers of rational formulation development. Finally, we propose a formulation-oriented framework for microbiome-aware oral drug delivery, outlining strategies to protect drugs from microbial degradation, harness microbial metabolism, or reshape the microbiome to support precision and safer therapeutics.