# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 2 Small Molecules
### Immunosuppressants
#### 2.2.2 Microneedles  
MNs are capable of different types of drug delivery, both small molecules and biological agents, for various kinds of diseases, such as cardiovascular disease, tissue regeneration, and immune-mediated diseases [56]. Invasive and noninvasive soluble microneedles have become the most studied form of microneedles due to their advantages of simple manufacture, safe handling, diverse materials, good biocompatibility, and high drug loading. Once applied to the skin, the needle dissolves to mediate immediate, controlled, or continuous delivery of the drug [57]. Currently, [PERSON] et al. reported the combination of methotrexate sodium (MTX Na) nanocrystals with soluble microneedles. MTX Na cannot be successfully administered subdermally because of hydrophilicity. The clearance rate of MTX Na is high, requiring more frequent administration to maintain the dose intensity, which may affect patient compliance. The MTX Na microneedles demonstrated excellent mechanical strength and effective penetration in skin simulations, fully dissolving within 20 min after application to porcine skin and delivering approximately one-quarter of the MTX to the psoriasis skin. Deposition of much larger amounts of MTX Na than oral MTX was achieved while minimizing systemic exposure to MTX [58]. [PERSON] et al. prepared silica nanoparticles with hollow structures, coated MTX in the cavity, and then adsorbed positive-potential chitosan onto the surface of microneedles. The silica MNs initially release 18% of drugs within 2 h, and the slow drug release process can last for 7 days, thus avoiding an outburst initial release profile and systematic blood vessel circulation [59]. Oxidative stress, NF-\(\kappa\)B, and adenosine are linked to signaling pathways involved in psoriatic inflammation. [PERSON] et al. developed a CD44-targeted MTX prodrug with ROS responsiveness designed to specifically target overactive keratinocytes. The nanocomposite of MTX prodrug combined with two polymers was created using a nanoprecipitation technique. To address the thickened stratum corneum in psoriatic skin, the nanocomposite was incorporated with soluble microrneedles by using a micro-molding method. The confocal laser scanning microscope (CLSM) image of HaCaT proved that nanoassemblies can be internalized by keratinocytes through a CD44-mediated pathway. The Franz diffusion cell experiment proved that the MTX prodrug encapsulated in microneedles can release 91.1% within 120 min, indicating that the prodrug can effectively penetrate the epidermis, subsequently inhibiting the hyperproliferation of keratinocytes by blocking the NF-\(\kappa\)B pathway. The immunoblotbolot analysis showed a 2.33-fold decrease in NF-\(\kappa\)B levels of inflamed skin tissue [60]. [PERSON] et al. prepared a microneedle array patch with expandable tips (TSMAP), incorporating micromeedle tips made of photo-crosslinked hyaluronic acid (MeHA) and a base constructed from biocompatible resin. Using vacuum drying, MeHA is concentrated at the tip of the needle to form an expandable tip that can be effectively loaded onto the tip after being incubated with MTX solution and then dried. Due to its good mechanical strength in piercing psoriasis-like skin, the tip of the loaded MTX can be separated from the matrix and released continuously and slowly as a drug reservoir. The comparative release experiment with fluorescein revealed that the dermal fluorescence signal of TSMAP persisted for 96 h before dissipating, which is significantly longer than that of the subcutaneous injection group [61]. [PERSON] et al. prepared cyclosporine-coated polyvinyl alcohol (PVA) microneedles using micro-molding and solvent-casting methods. The physical characteristics of the microneedles were investigated, and the drug encapsulation efficiency, release profile, skin penetration, and anti-posoriasis pharmacological activity of microneedles were evaluated.