Zein nanoparticles as emerging moderators of the gut microbiome: Mechanisms, biomedical potentials and translational challenges

Zein, a hydrophobic prolamin protein derived from maize, has emerged as a sustainable material for oral nanocarrier design due to its biodegradability, biocompatibility, and spontaneous self-assembly into stable NPs. This review critically examines the synthesis strategies, physicochemical behavior, and biological performance of zein NPs (ZNPs) with particular emphasis on gastrointestinal delivery and microbiome-associated outcomes. Current evidence indicates that ZNPs act primarily as protective and transport matrices: their intrinsic properties govern gastric resistance, mucus interaction, and controlled intestinal release, thereby improving stability and bioavailability of encapsulated compounds. The review insights into the microbiome pathway within a carrier-enabled exposure framework to correlate the attributing causality by ZNPs in the frame of the reported alterations in microbial composition, metabolite production, and host physiology arising from delivered bioactive (e.g., drugs, polyphenols, or probiotics). Moreover, the study details the advances in fabrication approaches, including desolvation, electrospraying, flash nanoprecipitation, and microfluidic micromixing, which have improved particle uniformity and scalability, supporting applications in pharmaceutical and nutraceutical delivery. Several studies demonstrate enhanced intestinal targeting, prolonged residence time, and reduced systemic toxicity in inflammatory and metabolic disease models. However, translation remains limited by incomplete mechanistic mapping of carrier-cargo-microbiome interactions, a lack of standardized large-scale manufacturing protocols, and insufficient long-term safety assessment under repeated oral exposure. Future progress will require integrating empty-carrier controls, longitudinal microbiome analyses, harmonized production standards, and nano-specific regulatory evaluation frameworks. Establishing these criteria will enable rational design of zein-based systems as controlled oral delivery platforms rather than assuming intrinsic microbiome-modulating activity.