Microbiome-aware oral drug delivery: excipient-microbiome interactions and nanocarrier design rules for predictable formulation performance.

Oral drug delivery remains the predominant administration route, but formulation strategies rarely account systematically for the gut microbiome. The microbiome can alter drug metabolism, excipient behavior, nanocarrier interactions, and interpatient variability. This review integrates evidence on microbial drug metabolism, excipient-microbiome interactions, nanocarrier engineering, microbiota-responsive delivery, and experimental models. Clinically relevant examples include digoxin inactivation by Eggerthella lenta, bacterial levodopa metabolism, and microbial beta-glucuronidase-mediated irinotecan toxicity. Microbiota-degradable polysaccharides may serve as colon-targeted release triggers, whereas some surfactants and polymers may create context-dependent microbiome or barrier risks. Nanocarrier size, charge, coating, mucoadhesion, mucus penetration, biodegradability, enzyme responsiveness, and surfactant burden are treated as microbiome-interface variables. We propose an authors' evidence-informed framework comprising an excipient classification, nanocarrier design rules, microbiota-responsive decision logic, and a tiered testing roadmap. These proposals are not established regulatory classifications; they are intended to support more predictable and patient-relevant oral formulation development.