# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 3 Biomacromolecules
### Nucleic Acid
#### 3.2.1 RNAi Therapy
To improve endosomal escape and minimize nanocarrier leakage, the nanoparticles incorporated a cationic surfactant, facilitating binding with anionic siRNA. The knockdown efficiency of interleukin-6 levels in keratinocytes and macrophages was around 60% and 70%. In the Franz experiment, the fractional laser promoted the skin deposition of nanoparticle siRNA up to 3.3 times and reduced IL-6 by 56%. The laser-assistednanocarrier alleviates erythema and squamous lesions in psoriatic dermatitis and reduces epidermal hyperplasia and immune cell infiltration [104]. Liquid crystal nanoparticles (LCNs) present a compelling option for topical drug delivery owing to their well-organized internal structure, expansive surface area, and resemblance to the skin's architecture. [PERSON] et al. used poly(allylamine hydrochloride) (PAH)-modified LCNs with reverse hexagonal microstructure (Figure 3A,B) to entrap tritptolide (TP), TNF-\(\alpha\), and IL-6 siRNA on its surface, aiming at local co-delivery in psoriasis treatment. When LCNs were embedded in hydroxyethyl cellulose hydrogels (LCN-TP), their co-delivery capacity was higher. The results of the IVPT experiment showed that TP was detected in pig skin, and the dermal distribution increased more than 20 times. In the efficacy study, LCNs showed good compatibility and rapid internalization, reducing the expression levels of TNF-\(\alpha\) by 11.4-fold, IL-6 by 3.88-fold, and IL-1\(\beta\) by 2.63-fold in lipopolysaccharideacharide (LPS)-stimulated macrophages (Figure 3C) [105]. [PERSON] designed NLCs for the delivery of tacrolimus (TAC) and siRNA-TNF-\(\alpha\) together, with a particle size of approximately 230 nm and a surface charge of +10 mV. In vitro skin penetration and retention experiments revealed that NLCs efficiently transport siRNA through the stratum corneum and improve the retention of tacrolimus within this layer. Finally, the expression of TNF-\(\alpha\) was shown to be decreased by about seven times in the psoriasis mouse model. Therefore, TAC and TNF-\(\alpha\) siRNA together can exert an amplifying effect on psoriasis [106]. Figure 3: (**A**) Schematic structure of LCNs. (**B**) Cryo-Transmission Electron Microscopy micrograph of LCNs prepared (1) without PAH polymer and (2) with PAH polymer (scale bar: 50 nm). (**C**) The quantitative results of downregulation efficiency of proinflammatory cytokines (TNF-\(\alpha\), IL-6, IL-1\(\beta\), and TGF-\(\beta\)1). Data shown are means \(\pm\) SD (n = 3/3 independent tests); two way-ANOVA, [PERSON]’s post-test: * \(p<\) 0.05; ** \(p<\) 0.01; *** \(p<\) 0.001, and *** \(p<\) 0.0001. Reproduced from Ref. [106]. (**D**) Schematic representation of formulation preparation of complex ionic liquids. (**E**) Quantification of the fluorescence intensities of different CIL preparations, implying the ability of keratinocyte internalization. Different columns in colors represent different ratios of complex siFn14-ionic liquid preparations. Data are expressed as mean \(\pm\) SD. ** \(p<\) 0.01. (**F**) Rate of transdermal water loss of siFn14-IL in 8 h. Reproduced with permission from Ref. [107]. (**G**) Three-dimensional structure of human IL-17A homodimer. The different colors represent different secondary structures of protein (blue represents \(\beta\)-pleated sheet; green represents \(\beta\)-turn). The schematic representation of the structure of (**H**) M2 aptamers and (**I**) M7. Multiple colors were used to distinguish bases. Reproduced with permission from Ref. [108]. [PERSON] et al. prepared hybrid nanoparticles composed of lipids and polymers, which can effectively entrap the photosensitizing agent meso-tetraphenyl porphyrin disulfonate (TPPS2a) and the siRNA (PLNs). Compared with the TPPS2a solution, PLNs had a 1267-time reduction in skin permeation, while skin retention was similar. This means that PLNs retain most drugs in the psoriasis lesion without allowing them to enter the systemic circulation.