# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 2 Small Molecules
### Immunosuppressants
#### 2.2.1 Hydrogel  
[PERSON] et al. proposed an external water gel based on iota-carrageenanan (iCR). \(\beta\)-cyclodextrintrin (\(\beta\)-CD) was incorporated into carrageenanan gel to form a clathrate with MTX, which significantly improved the solubility of MTX in water. The addition of \(\beta\)-CD accelerates the release of MTX, achieving 100 wt% within 4 h, whereas, without \(\beta\)-CD, the cumulative release is only 35 wt% over the same period. Transdermal transport experiments reveal that the presence of \(\beta\)-CD reduces the transport efficiency by 10% within 5 h. The inclusion of \(\beta\)-CD facilitates the rapid release of MTX while limiting its entry into the systemic circulation, thereby retaining a significant amount of MTX at the psoriatic lesion site and enabling long-lasting therapeutic effects [47]. Photodynamic therapy (PDT) has long been accepted as a noninvasive and cosmetically favorable treatment for psoriasis. ALA (5-aminolevulinic acid), as a photosensitizer for PDT, has been approved by the FDA. Externally administered ALA is converted inside cells into the photosensitive compound protoporphyrin IX (PpIX). When exposed to light, the accumulated PpIX produces reactive oxygen species (ROS) that trigger cell transition to apoptosis and necrosis in the targeted tissue, which aligns with the therapeutic goal of inhibiting cell proliferation in psoriatic lesions. Due to the complexity of psoriasis pathology, it often exhibits insufficient responsiveness to monotherapy. To achieve better therapeutic outcomes, drug-photodynamic combination therapy has gained increasing attention from researchers. To overcome the skin barrier in psoriasis, [PERSON] et al. created a nanogel by combining chitosan and hyaluronic acid for the topical administration of MTX and ALA. While the compound suspension only penetrated 20 um into the epidermis, the nanogel achieved a deeper penetration of 70 um. The apoptosis rates for LPS-induced HaCaT cells were 50.2% with the suspension and 78.6% with the nanogel. Additionally, nanogel reduced TEWL (transepidermal water loss) values to 16.20 \(\pm\) 0.98 g/m\({}^{2}\)-h [48]. A zinc nanospheres were reported previously by [PERSON] et al. [49]. [PERSON] et al. reported a composite hydrogel with multiple synergistic effects in the treatment of psoriasis. The gel contains good biocompatible zinc mesoporous nanospheres, and Ag nanoparticles are evenly dispersed in the nanospheres (denoted as ZnO/Ag or ZA). Silver nanoparticles enhance the immunomodulatory properties of ZA by inhibiting cytokines associated with innate immunity and modulating the STAT3-cyclin D1 pathway through the removal of ROS, thereby suppressing the self-amplifying behavior of cytokines that are linked to adaptive immunity (Figure 2A). Simultaneously, the microspheres are integrated with methotrexate to enable the sustained release of MTX. The MTX-zinc (MTX-ZA) microspheres, modified with nanomicelles and incorporated into Carbopol, form the MTX-zinc hydrogel. The MTX-zinc hydrogel showed a long skin retention time over 24 h (Figure 2B). In the IMQ-induced mouse model, the spleen weight index of the plain MTX-ZA hydrogel-treated group is 8.97 \(\pm\) 0.53; the value of the MTX-ZA hydrogel-treated group is 2.95 \(\pm\) 0.13, which showed a better therapeutic effect [50]. Ionic liquids consist of organic cations incorporated with organic or inorganic anions. Recently, ILs formed from choline cations and organic acid anions have gained attention due to their numerous advantageous properties. Choline and pelargonic acid (CAGE) are selected to form ionic liquids. Microemulsion is a thermodynamically stable solution composed of amphiphilic components that contain micrometer-sized droplets. Ionic liquid microemulsion combines both ILs and microemulsion solutions to solubilize poor-solubility drugs and enhance penetration. Figure 2: **(A)** The construction process and therapeutic mechanisms of MTX-ZA hydrogel.