A Hyaluronic Acid-Stabilized Zinc-Loaded Probiotic Mitigates Nanoplastic Toxicity across the Microbiota–Gut–Brain Axis

Abstract Nanoplastics are emerging stressors that perturb host physiology across the gut–immune–brain continuum, yet scalable interventions remain limited. Here, we engineer ZG@EcN@HA, a biohybrid living system created by vacuum-assisted intracellular loading of zinc gluconate into Escherichia coli Nissle 1917 (EcN) followed by an outer hyaluronic acid (HA) shell. This architecture preserves probiotic culturability under gastric challenge and supports sustained zinc availability in intestinal conditions. In zebrafish chronically exposed to polystyrene nanoplastics, we observe reproducible neurobehavioral impairment coupled with inflammatory activation, redox imbalance, barrier stress, neurotransmitter dysregulation, and multiorgan histopathology. ZG@EcN@HA yields the most coherent rescue compared with single-component controls, restoring behavioral outputs and realigning immune–redox–neurochemical readouts. ASV-based profiling shows recovery of microbial diversity and a shift toward a control-like community structure, including reduced dominance of inflammation-linked taxa. Intestinal transcriptomics and integrative correlation analyses further support normalization of barrier/metabolic programs and attenuation of innate inflammatory signaling. Together, the data identify a materials-enabled strategy for microbiota–gut–brain protection against chronic nanoplastic stress.