# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 2 Small Molecules  
### Corticosteroids  
#### Micro/Nanocarrier-Loaded Hydrogels  
Corticosteroids are the primary treatment for all severity levels of psoriasis, used either alone or alongside systemic therapies. They exert their therapeutic effects via nuclear receptor interactions and rapid non-receptor-mediated mechanisms. The nuclear receptor interactions involve glucocorticoid receptors (GRs) activated by cortisol, leading to receptor homodimerization and binding to glucocorticoid response elements (GREs). In the absence of ligands, GRs remain in the cytoplasm, bound to proteins. Ligand binding disrupts this complex, allowing GRs to translocate to the nucleus. Upon dimerization and binding to GREs, GRs promote the transcription of genes that secrete anti-inflammatory cytokines. In contrast, rapid non-receptor-mediated mechanisms involve combining with membrane receptors, which mediates rapid glucocorticoid effects within minutes by second messengers. This pathway does not rely on protein synthesis but modulates the activity of monocytes, T cells, and platelets [24; 25; 26]. Corticosteroids are formulated in various preparations, especially ointments and creams. The choice of excipient can significantly influence the therapeutic and adverse effects by altering the pharmacokinetics of the corticosteroid. Consequently, the development of advanced and innovative delivery systems for corticosteroids is a major focus in pharmaceutical research [27]. At present, the main dosage form of corticosteroids on the market is ointment. Compared with ointment, hydrogel is aqueous; it leaves no residue, provides good moisturization, and has a non-greasy texture, making it favorable. Hydrogels can also maintain skin hydration, prevent itching, and provide a prolonged drug contact time. Additionally, hydrogels can be combined with liposomes, vesicles, solid lipid nanoparticles, and nanocarriers to enhance skin retention, penetration, and release profiles of drugs [28]. [PERSON] et al. developed a temperature-sensitive polymer-based dexamethasone (Dex) prodrug named ProGel-Dex. The dexamethasone molecule is connected to the HPMA molecule via a hydrazone bond, which endows ProGel-Dex with the ability to cleave under acidic conditions and activate at the lesion site. Its phase transforms from liquid at 4 \({}^{\circ}\)C to gel above 30 \({}^{\circ}\)C. Experimental results showed that the low-dose administration group (L group) could reduce the PASI score (Psoriasis Area and Severity Index) to below 2, which is significantly lower compared with the score of 5 observed in the imiquimod (IMQ)-induced modeL group. Histological hematoxylin-eosin staining (H&E staining) results revealed a reduction in epidermal thickness in the low-dose group. Enzyme-linked immunosorbent assay (ELISA) measurements of serum inflammatory factors indicated that the L group reduced IL-6 levels from 20 pg/mL to 0 pg/mL. The efficacy of ProGel-Dex in alleviating skin inflammation can be attributed to the reduction in serum IL-6 levels [29]. [PERSON] et al. prepared hydrogenated cortisol-loaded sorbitan monostearate-polycaprolactone nanoparticles (HCT-SMS-PCL), which were encapsulated in a temperature-sensitive gel composed of thermosensitive carboxymethyl cellulose (CMC). The encapsulation efficiency (EE) of nanoparticles was 76%. The tube inversion method results indicated a state transition temperature of 33 \(\pm\) 2 \({}^{\circ}\)C, suggesting its capability for drug delivery at physiological temperatures. The release rates of nanoparticles and hydrogel at pH 5.9 were 83.9% and 81.9%, indicating favorable drug release properties [30]. Traditional topical corticosteroid formulations face limitations, including inefficient drug encapsulation, outburst release, limited skin penetration, and potential toxicity concerns. Here, [PERSON] et al. made a soft hydrogel (B-gel) for the localized delivery of betamethasone by conjugating glycine dipeptide with hydrophilic cholic acid.