A dual functional hybrid lipid-polymeric nanoparticle co-loaded coenzyme Q10 and siRNA TNFα for anti-inflammatory...

Inflammatory skin diseases, such as psoriasis, lead to significant humanistic and economic burdens, mainly psychosocial impacts due to the relapsing papulosquamous characteristic of the disease. Due to the extensive skin lesions, topical therapies remain the main form of treatment. However, their effectiveness is limited by poor skin penetration. In addition, single-target mechanisms limit the simultaneous modulation of inflammatory and oxidative pathways involved in the pathogenesis of psoriasis and other skin diseases. To overcome these limitations, we developed hybrid lipid-polymeric nanoparticles (HLPNs) for the co-delivery of coenzyme Q10 (CoQ10), an endogenous antioxidant with anti-inflammatory properties, and small interfering RNA (siRNA) targeting TNFα, a central pro-inflammatory cytokine. HLPNs exhibited particles of 150-250 nm with low polydispersity (0.08-0.16), and high CoQ10 encapsulation efficiency (>85%). The presence of poly(allylamine hydrochloride) reversed the zeta potential (-27 to + 20 mV), enabling high siRNA binding efficiency and RNase protection. Structural analysis (ATR-FTIR, DSC, PXRD) confirmed successful CoQ10 incorporation into the lipid matrix and its amorphous conversion. HLPNs enhanced CoQ10 penetration into the stratum corneum (2-4.5-fold) and viable epidermis/dermis (4.7-7.5-fold) compared to solution, while confocal microscopy demonstrated improved siRNA skin delivery. In cell culture, HLPN-siRNA complexes promoted robust siRNA uptake in keratinocytes and macrophages. Therapeutic efficacy was validated in LPS-stimulated RAW264.7 macrophages, where HLPN_CoQ10-siTNFα significantly suppressed TNFα (3-6.5-fold), IL-6 (2-2.7-fold), and IL-1β (1.3-3-fold) secretion, while preserving CoQ10's antioxidant capacity and reducing reactive oxygen species (1.3-1.5-fold). Collectively, these findings show that the dual lipid-polymeric nature of HLPNs enables combinatorial delivery of antioxidant and RNAi therapies, offering a promising strategy for complex inflammatory skin disorders.