Spatiotemporally controllable delivery of siRNA enables synergetic gene and mild-photothermal therapy for psoriasis

Psoriasis is a chronic inflammatory dermatosis with excessive activation of toll-like receptors (TLRs). Small interfering RNA (siRNA) has been considered a promising therapeutic approach by significantly suppressing mRNA expression. However, the low skin barrier penetration and the poor stability of siRNA pose a key challenge. Herein, we developed a novel and near-infrared (NIR) activated nanosystem (termed as GD-siMYD88@SPN/DA) that utilizes the gold nanorod (GNR) with highly photothermal conversion efficiency to realize localized thermal effects and photothermal-controlled release of siMYD88. Meanwhile, the shell grafted desmosome core-glycoprotein3 (Dsg3) antibody endowed it with the ability to target keratinocytes. The endocytosis of GD-siMYD88@SPN/DA by HaCaTs was significantly higher than that of the non-targeted nanosystem (GD-siMYD88@SPN), and the GD-siMYD88@SPN/DA exhibited enhanced stability in the skin. The double strand formed by the GNR-linked DNA fragment and siMYD88 serves as controlled element in response to photothermal stimulation, achieving controlled release of siMYD88. Knockdown of the MYD88 gene could effectively inhibit the TLR/MYD88/NF-κB signaling pathway, thereby reducing the production of psoriasis-related inflammatory factors. Notably, the synergistic therapeutic effects of mild-photothermal therapy combined with GD-siMYD88@SPN/DA were observed both in vitro and in vivo . Overall, this spatiotemporally controllable approach provides a versatile strategy for controllable gene therapy and mild-photothermal therapy for psoriasis.