Liquid crystalline nanoparticles enable a multifunctional approach for topical psoriasis therapy by co-delivering triptolide and siRNAs

Schematic illustration of the multifunctional-LCN production and intracellular delivery. siTNF-α and siIL-6 promote cleavage of the messenger RNA (mRNA) target of TNF- α and IL-6 proteins, leading to downregulation of these proteins and reducing extracellular levels. Additionally, TP acts on subunits of RNA polymerase II (RNApol II) inhibiting the transcription of mRNAs of pro-inflammatory signaling pathways. [Display omitted] •LCNs based on reverse hexagonal liquid–crystal rationally designed for topical co-delivery of TP, siTNF-α and siIL-6.•LCNs in hydroxyethylcellulose hydrogel increases in vitro skin retention of TP and siRNAs.•TP encapsulation in LCNs improved the cytotoxic profile and increased its anti-inflammatory effects.•LCNs showed rapid internalization and endosomal escape, important for the effectiveness of the gene delivery.•Synergistic effect in the reduction of TNF-α, IL-1β and IL-6 with multifunctional LCNs in in vitro inflammatory model. Liquid crystalline nanoparticles (LCNs) are an attractive drugs topical delivery system due to the great internal ordering, wide interfacial area and structural similarities with the skin. In this work, LCNs were designed to encapsulate triptolide (TP) and to complex on its surface small interfering RNAs (siRNA) targeting TNF-α and IL-6, aiming at topical co-delivery and regulating multi-targets in psoriasis. These multifunctional LCNs showed appropriate physicochemical properties for topical application, such as a mean size of 150 nm, low polydispersion, TP encapsulation greater than 90% and efficient complexation with siRNA. The internal reverse hexagonal mesostructure of LCNs was confirmed by SAXS while their morphology was assessed by cryo-TEM. In vitro permeation studies revealed an increase of more than 20-fold in the distribution of TP through the porcine epidermis/dermis was achieved after the application of LCN-TP or LCN TP in hydrogel. In cell culture, LCNs showed good compatibility and rapid internalization, which was attributed to macropinocytosis and caveolin-mediated endocytosis. Anti-inflammatory potential of multifunctional LCNs was assessed by reducing of TNF-α, IL-6, IL-1β and TGF-β1 levels in LPS-stimulated macrophages. These results support the hypothesis that the co-delivery of TP and siRNAs by LCNs may be a new strategy for psoriasis topical therapy.