Nanoparticles and the gut-microbiome: a dual strategy for oral brain delivery.

The blood-brain barrier (BBB) remains a major physiological challenge in the treatment of central nervous system (CNS) disorders. Most existing drug delivery strategies primarily focus on overcoming the BBB itself, while largely neglecting upstream barriers encountered during oral administration, including the intestinal mucus layer and microbiome-derived metabolism (MDM). In this review, we propose a broader conceptual framework in which the BBB is viewed as an integral component of a continuous and dynamic system shaped by the gut-microbiota-brain axis. Herein, current oral-to-brain delivery platforms are critically evaluated, ranging from synthetic organic and inorganic nanoparticles to emerging pathogen-inspired systems, with particular emphasis on bacterial extracellular vesicles (BEVs). Owing to their biological origin, BEVs exhibit intrinsic barrier-navigation capabilities, enabling efficient translocation across intestinal and cerebral interfaces. However, effective CNS drug delivery also requires consideration of inter-individual variability in microbiome composition and metabolic function, which can profoundly influence drug bioavailability and efficacy. By integrating advances in synthetic biology and human-relevant organ-on-chip platforms, this review highlights emerging strategies to address microbiome-driven variability and improve translational predictability. Collectively, these approaches support the development of next-generation oral CNS therapeutics that move beyond standardized formulations toward precision microbiome-pharmacology, with potential implications for the treatment of neurodegenerative and neuropsychiatric disorders.