# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 3 Biomacromolecules
### Nucleic Acid  
#### 3.2.1 RNAi Therapy  
Targeting the RNA interference (RNAii) pathway offers a way to modify disease-related biological processes in various medical conditions, including autoimmune disorders. Large-scale genome-wide association studies have identified over 80 genetic loci linked to psoriasis susceptibility [100]. In psoriasis, RNAi can suppress the expression of molecules involved in the disease's pathogenic mechanisms. However, delivering siRNA to the target site without adverse effects remains challenging. Barriers to RNA delivery include carrier collapse in the bloodstream, renal clearance, binding to plasma proteins, entrapment by the mononuclear phagocytic system (MPS), and membrane impermeability. Intracellularly, endosomal entrapment after cellular uptake is a major obstacle [93]. A successful siRNA delivery system should fulfill several essential requirements: (1) protect siRNA against degradation within the body; (2) traverse the endothelium to access target tissues; (3) allow for regulated siRNA release; (4) promote efficient cellular uptake; and (5) ensure proper endosomal escape and cytoplasmic delivery of siRNA to enable the formation of the RNA-induced silencing complex (RISC) for functional activity. Progress in biomaterials science has driven the creation of synthetic lipids and polymers that effectively tackle numerous obstacles in siRNA delivery. These materials provide a foundation for designing safe, effective, and clinically viable siRNA delivery systems. Significant progress has been made in RNAi-based therapies for psoriasis [101]. Tetrahedral framework nucleic acid (tFNA) has become an excellent transdermal carrier for gene transport due to its noninvasive and editable properties. Tannic acid (TA) is a natural compound that has anti-inflammatory and antioxidant activity. TA can incorporate with nucleic acids through hydrogen bonds and mediate the size regulation of nucleic acid delivery nanomaterials. [PERSON] et al. created a complex assembled using TA, tFNA, and siRNA named STT. STT enters the lysosome through caveolin protein-mediated endocytosis and releases the drug via hydrogen bond dissociation under the regulation of lysosomal acid. STT inhibited the secretion of interleukin-17 and 23 and TNF-\(\alpha\) by silencing the NF-kB pathway, breaking the closed-loop inflammatory cycle. Additionally, STT helps restore the skin's immune balance by curbing the overgrowth of keratinocytes, decreasing the secretion of numerous inflammatory mediators via dendritic cells, and limiting the transformation and differentiation of mDCs [102]. [PERSON] et al. designed self-assembled \"sandwich\" structured nanoparticles based on methoxy-pegylated poly-histidine (mPEG-pHis) and methoxy-pegylated polylactic acid (mPEG-PLA) that have the ability to adsorb specific disease proteins, allowing the nanoparticles to accumulate in peripheral inflammatory immune cells. After intravenous injection, psoriasis-specific proteins and autoungrens in peripheral blood automatically cover the nanoparticles, enabling the uptake percentage of CD11b+ to increase by 50%. The protein corona allowed the nanoparticles to bind to formylpeptide receptors and Toll-like receptors (TLR-4), facilitating therapeutic localization in PBMCs and ultimately facilitating the localization of the nanoparticles into psoriasis lesions, supplied by the results of flow cytometry. Systemic oxidative stress triggers the step release of \"sandwich\" nanoparticles. MTX and siRNA-TNF-\(\alpha\) combine to play anti-inflammatory effects, causing a reduction in the percentage of proliferating HaCaT cells from 19.1% to 10.1%. The catabolism of histidine can also promote the sensitivity of cells to MTX by upregulating folate 2.5 times. Considering all of this, nanoparticles can block the skin-homing effect of immune cells and regulate the systemic immune microenvironment [103]. [PERSON] et al. developed a PLGA nanoparticle that delivers siRNA. Researchers utilized bioengineering technology (heat laser) to promote skin absorption.