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

ABSTRACT The development of effective drug delivery systems for subcutaneous or intradermal injection requires systems with improved bioavailability and biocompatibility. Systematic physicochemical and biological interrogation of carnauba‐wax/red‐palm‐oil lipid nanoparticles (LNPs) stabilized 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 reveal hybrid morphology dominated by 30–40 nm toroidal disc‐shaped particles. Orthogonal analytics via multidetection asymmetrical flow field‐flow fractionation and WAXS confirm that loading with quinine or dihydroartemisinin leaves size and crystallinity unchanged, achieving approximately 90% encapsulation efficiencies and particle stability up to 18 months at 4°C. Formulations containing red palm oil and the dual‐surfactant corona exhibited reduced size dispersity compared with single‐component formulations. Long‐term viability assays in primary human fibroblasts and macrophages, and ex vivo cultured human skin, underscore excellent biocompatibility up to 0.024% (w/v) lipid. Fluorescein‐labeled LNPs traversed the dermis and hypodermis, while only nanomolar lipid concentrations appeared in the receiver medium, indicating a sustained local depot. Overall, this study provides insights into the relationship between formulation composition, particle morphology and measured physicochemical and biological properties relevant to under‐skin administration.