Digestive-transformed titanium dioxide nanoparticles disrupt intestinal barrier via mitoxyperilysis mediated by...

Titanium dioxide nanoparticles (TiO₂ NPs) are ubiquitous dietary additives, yet their impact on the intestinal barrier remains contentious, largely because conventional toxicological models overlook gastrointestinal digestive transformations. Characterization revealed that pristine TiO₂ NPs exist as nanoscale aggregates, which, upon simulated digestion, lose electrostatic repulsion and expand into dense, biocorona-coated, micrometer-sized agglomerates enriched in nitrogen and phosphorus. While these transformed entities induce severe barrier dysfunction, the spatiotemporal mechanisms executing plasma membrane rupture remain a critical knowledge gap in nanotoxicology. Here, we uncover a non-canonical, spatially dependent cell death modality termed mitoxyperilysis as the core driver of TiO₂ NPs-induced nanotoxicity, operating independently of classical apoptosis, ferroptosis, necroptosis, and pyroptosis. We demonstrate that exposure to digested TiO₂ NPs agglomerates hyperactivates the protein kinase B (AKT)/mechanistic target of rapamycin complex 2 (mTORC2)-RhoA signaling axis, leading to widespread F-actin cytoskeletal paralysis. This structural breakdown dismantles intracellular spatial constraints, enabling ROS-emitting, dysfunctional mitochondria to aberrantly translocate and persistently tether to the plasma membrane, deploying high concentrations of mitochondria-derived ROS (mtROS) locally. Quantitative lipidomics of plasma membrane fractions reveals that this targeted mtROS assault induces severe depletion of membrane-stabilizing lipids and the explosive generation of oxidized lipid mediators, culminating in lytic membrane failure. Ultimately, this nanotoxicology study decodes a novel nano-mechanopathological paradigm dictated by mTOR-cytoskeleton dysregulation and localized mitochondrial lipid peroxidation, providing critical translational insights and therapeutic targets for mitigation.