# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 2 Small Molecules
### Retinoids  
#### 2.3.1 Liposome and Transethosome (Vesicles)  
At the cellular level, retinoic acid inhibits the generation of proinflammatory Th17 cells mediated by IL-6, promotes the differentiation of Treg cells, and suppresses excessive immune responses. The limitations of the clinical application of retinoic acid are mainly reflected in low water solubility, photosensitivity, and skin irritation. Intravenous administration increases catabolism, reduces therapeutic effectiveness, and increases systemic side effects [73]. [PERSON] et al. developed a nano-transdermal delivery system comprising all-trans retinoic acid (TRA) and gel. The TRA nanoparticles, synthesized using the reverse micelle method, exhibit strong mitochondrial targeting and valence transition capabilities linked to reactive oxygen species (ROS) scavenging. The TRA gel system, prepared using the thin film dispersion method, can effectively encapsulate the drug. The TRA gel formulation extended drug release to 72 h, whereas the free TRA gel released nearly all of the drug within 8 h. Additionally, skin retention improved by 1.81 times. The EGF induction and the H\({}_{2}\)O\({}_{2}\) induction showed that the TRA gel efficiently downregulated inflammatory levels of HaCaT cells and alleviated oxidative stress. The results of the IMQ-induced in vivo model showed that the TRA gel significantly alleviated psoriasis symptoms [74]. Retinoic acid systems often lead to significant systemic side effects, and their topical application is restricted due to low water solubility and skin irritation. To address these issues, [PERSON] et al. developed a fatty acid vesicle encapsulating retinoic acid (Tre-FAV). The drug encapsulation reached 84.26 \(\pm\) 0.816%, and the surface charge was \(-\)28.9 \(\pm\)1.92 mV. The skin retention of Tre-FAV increased by 2.89 times compared with the solution form. In mouse models, the topical application of Tre-FAV demonstrated superior anti-sporiatic effects, effectively reducing papules, erythema, and epidermal thickness. Spleen weightdecreased post-treatment, and serum levels of proinflammatory cytokines were significantly reduced [75]. Bexarotene is one of the retinoids that exerts a better therapeutic effect on psoriasis, but its poor solubility and skin irritation make it difficult to administer via the topical route. In order to overcome these shortages, [PERSON] et al. incorporated it into liposomes to solve these problems. This study focused on optimizing the preparation of bexarotene liposomes by adjusting key factors, including the compound ratio, sonication time, drug content, and loading capacity. The optimized liposomes, with a particle size of 67.8 \(\pm\) 7.15 nm, were integrated into a gel, achieving an encapsulation efficiency exceeding 95%. Pharmacology studies using the BALB/c mouse psoriasis plaque model induced using imiquimod confirmed that bexarotene liposomes can effectively treat psoriasis by reducing scale and inflammation without any toxicity. After treatment, TNF-\(\alpha\), IL-17, IL-22, IL-23, and IL-2 decreased by 1.94, 1.96, 2.49, 1.40, and 2.14 times compared with a negative control [76]. At present, the mainly oral formulations of acitretin A in the market for psoriasis are not effective and have serious teratogenicity and other systemic side effects. Skin irritation is one of acitretin's adverse reactions. [PERSON] et al. developed gel formulations based on elastic liposomes and ethosomes, which have deformable capabilities and higher skin permeability compared with nanoparticles. Elastic liposomes and ethosomes were integrated with Carbopol 934 to assess the appearance. The skin irritation score of liposome gel (lipogel) and ethosome gel (ethogel) was below 0.9, while the commercial acitretin gel (plain gel) caused erythema and edema. An in vivo localization test showed that the skin localization index values of lipogel and ethogel were higher at 39.5% and 36.1%, compared with plain gel, which was 17.5%.