Cell Targeting and Adjuvant Activity of Dietary Titanium Dioxide

Wills, J. W.; Dabrowska, A.; Robertson, J.; Miniter, M.; Riedle, S.; Summers, H.; Hewitt, R.; Fathima, A.; Barreto da Silva, A.; Bastos, C.; Micklethwaite, S.; Keita, A.; Soderholm, J.; Roy, N.; Otter, D.; Jugdaohsingh, R.; Mastroeni, P.; Brown, A. P.; Rees, P.; Powell, J. J.

doi:10.1101/2024.04.16.589772

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.16.589772

Cell Targeting and Adjuvant Activity of Dietary Titanium Dioxide

View original source ↗Export metadata ↓

Abstract

Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Paradoxically, meaningful in vivo cellular accumulation has never been demonstrated: the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify major new immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyers patches. Using multimodal microscopy techniques with single-particle detection and per-cell / vesicle image analysis we achieved correlative dosimetry, quantitatively recapitulating human cellular exposures in the terminal ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funneled fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets revealed no measureable perturbation of cell signalling pathways. When chased with oral {Delta}aroA-Salmonella, pro-inflammatory signalling was confirmed, but no augmentation by fgTiO2 was revealed despite marked same-cell loading. Interestingly, Salmonella caused the fgTiO2-recipient cells to migrate basolaterally in the patch and, sporadically, to the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. Immunocompetent cells that accumulate fgTiO2 in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.

Source connections

Published article ↗

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Wills, J. W., Dabrowska, A., Robertson, J., Miniter, M., Riedle, S., Summers, H., Hewitt, R., Fathima, A., Barreto da Silva, A., Bastos, C., Micklethwaite, S., Keita, A., Soderholm, J., Roy, N., Otter, D., Jugdaohsingh, R., Mastroeni, P., Brown, A. P., Rees, P., Powell, J. J.. 2024-04-20. Cell Targeting and Adjuvant Activity of Dietary Titanium Dioxide. https://doi.org/10.1101/2024.04.16.589772

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗

bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

bioRxiv2025

Mapping cellular targets of covalent cancer drugs in the entire mammalian body

As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the 3D mammalian body. With simple and passive incubation steps, vCATCH offers cellular resolution drug imaging in the entire adult mouse. We combined vCATCH with HYBRiD imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.

pharmacology and toxicology↗