# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 4 Cell-Based Therapy
### Extracellular Vesicles  
Over the past few years, small extracellular vesicles (sEVs) have been explored as cell-free immunomododulators. In fact, unmodified or engineered sEVs have been affirmed to have therapeutic potential in different types of diseases, including cancer, inflammatory lung disease, and autoimmune diseases. The programmed cell death of protein 1 and its ligand (PD-1/PD-L1) signaling axis play an essential role in preserving immune homeostasis by suppressing both the initiation and effector stages of immune reactions. Evidence suggests that dysfunctional PD-1/PD-L1 signaling is closely associated with the development of autoimmune disorders. Augmentation of the PD-1/PD-L1 binding capacity has been demonstrated to suppress the expansion and activation of antigen-targeted T lymphocytes and B lymphocytes while concurrently curbing the secretion of inflammatory cytokines. Recently, [PERSON] et al. developed bone marrow-derived MSC extracellular vesicles that highly expressed PD-L1 using lentiviral transfection and puromycin screening, achieving an average diameter of 100 nm. This minimal size lowered the risk of thrombosis and vascular blockage. The researchers observed that MSC-sEV-PD-L1 treatment alleviated skin redness and scaling and significantly reduced acanthosis, parakeratosis, and epidermal thickening. Additionally, vasodilation and immune cells were diminished from the skin [137]. [PERSON] et al. introduced umbilical cord-derived sEVs (UCB-sEVs). These vesicles induced M2 macrophage polarization, which subsequently influenced skin fibroblasts, reducing their reactivity to inflammatory signals. UCB-sEVs reduced the number of CD8+ T cells infiltrated while increasing Treg cell populations. Furthermore, UCB-sEV treatment significantly lowered the level of inflammatory molecules, such as interferon and chemokine, as well as antimicrobial peptides. UCB-sEV treatment also promotes a transformation from T helper cells to regulatory T cell phenotypes, restoring local immune balance and demonstrating the potential for psoriasis treatment [138]. [PERSON] et al. proposed a new therapeutic strategy for psoriasis using JPH203-loaded extracellular vesicles derived from UVB-irradiated keratinocytes (J@EV). JPH203, a specific LAT1 inhibitor, blocks leucine uptake to suppress mTOR signaling. J@EV exhibited enhanced uptake in inflamed HaCaT cells, with 250% upregulation in fluorescence intensity compared with normal cells after one hour of incubation. J@EV reduced epidermal thickening by 77% and decreased the Th17 cell ratio in the spleen from 19.6% to 4.25% compared with the IMQ group. J@EV also suppressed the phosphorylation of mTOR, reducing the p-mTOR/mTOR ratio by 60%. In summary, J@EV demonstrated potent therapeutic efficacy in psoriasis by targeting the vicious \"Inflammation-Th17-Keratinocytes\" cycle, with significant reductions in epidermal thickness, PASI scores, and immune cell activation while maintaining good biosafety [139]. At present, researchers are focusing not only on the disturbance of the immune system in psoriasis but also on the disturbance of the skin microbiome, which plays an increasingly prominent role in psoriasis. Bacterial extracellular vesicles play an important regulatory role in host-microbiome interactions. [PERSON] et al. extracted extracellular vesicles (CA-EVs) derived from _Ctibacterium acnes_ (_C. acnes_), embedded them in gelatin methacrylate (CA-EV-G), and prepared hydrogel microsBpheres (CA-EV-M) with an average diameter of 358.06 \(\pm\) 22.06 \(\upmu\)m (Figure 4A,B). CA-EV-M presented the sustained release of CA-EVs, with about 80% of the total protein content within 4 days (Figure 4C,D). The epidermal thickness decreased from 120 \(\upmu\)m in the IMQ group to 60 \(\upmu\)m in the CA-EV-M group. TEWL was reduced by 50% in the CA-EV-M group compared with the IMQ group. The EVs of _Staphylococcus epidermidis_ play a role in regulating the immune environment by interacting with the host skin [140]. [PERSON] et al.