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bioRxiv · 10.1101/2025.07.20.665764

Disc-Toroid Hybrid Lipid Nanoparticles for Efficient Drug Encapsulation and Subcutaneous Delivery

Van Niekerk, Z.·Nuwayhid, R.·Gaydarova, S.·Bittrich, E.·Makarova, N.·Boye, S.·Formanek, P.·Tzachev, C.·Simon, J.-C.·Franz, S.·Lederer, A.
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Abstract

The development of an effective for subcutaneous or intradermal injection drug delivery requires systems with improved bioavailability and biocompatibility. Systematic physicochemical and biological interrogation of carnauba-wax/red-palm-oil lipid nanoparticles (LNPs) stabilised with d--tocopheryl-PEG-1000-succinate and polysorbate-40 shows that purposeful matrix engineering yields a robust sub-50 nm carrier for under-skin delivery. Cryo-TEM and SAXS uncover a disc-toroid hybrid morphology dominated by 30-40 nm particles with toroidal/disc shape - an advantageous biconcave geometry to enhance surface-to-volume ratio and is expected to accelerate enzymatic erosion after injection. Orthogonal analytics (AF4-MD, DLS, MALS, WAXS) confirmed that loading with quinine or dihydroartemisinin leaves size and crystallinity unchanged while delivering encapsulation efficiencies of approximately 90 % and long-term particle stability up to 18 months at 4 {degrees}C. Red-palm oil and the dual-surfactant corona act synergistically to suppress bimodality and narrow size distribution compared with single-component controls. Short-term viability assays in keratinocytes, fibroblasts and macrophages showed no cytotoxicity even at [≥]1 % (w/v) lipid, underscoring excellent biocompatibility. Fluorescein-labelled LNPs injected into ex vivo human skin traversed the dermis and hypodermis, while only nanomolar lipid concentrations appeared in the receiver medium, indicating a sustained local depot. Collectively, these insights link composition, structure and performance, positioning wax-based disc-toroid LNPs as a flexible platform for high-load delivery of small-molecule or biopharmaceutical therapeutics via minimally invasive under-skin administration.

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Van Niekerk, Z., Nuwayhid, R., Gaydarova, S., Bittrich, E., Makarova, N., Boye, S., Formanek, P., Tzachev, C., Simon, J.-C., Franz, S., Lederer, A.. 2025-07-20. Disc-Toroid Hybrid Lipid Nanoparticles for Efficient Drug Encapsulation and Subcutaneous Delivery. https://doi.org/10.1101/2025.07.20.665764

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