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

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-α-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 °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.