Tumor-Derived PD-L1⁺ Exosomes with Natural Inflammation Tropism for Psoriasis-Targeted Treatment

Abstract

Background: Psoriasis is a chronic and readily recurrent in ammatory skin disease. To date, there is no cure for psoriasis and signi cant challenges remain in developing more safe and e cacious novel targeted therapies. Psoriasis is characterized by abnormal activation of the immune system, and hyperproliferation and aberrant differentiation of keratinocytes. Psoriatic keratinocytes death is also recently recognized as a major ampli er to the initiation of in ammatory cascade. Given that both keratinocytes and immune cells express high PD-1 in psoriasis, which imply PD-1 as a potential therapeutic target for psoriasis. Here, we developed a well-structured pristimerin nanodot-loaded PD-L1 positive exosome derived from tumor cells (Pri@exo) and elucidated their targeting therapeutic effects.Results: The Pri@exo displays strong cellular uptake and intracellular retention in active CD4 + T cells and HaCaT keratinocytes, suggesting the PD-1 + cells targeting capacity of Pri@exo. Remarkably, Pri@exo signi cantly and safely reversed imiquimod (IMQ)-induced psoriasis in mice, indicated by reducing epidermal thickness, decreasing plaque formation, and over-activating in ammation since it targeted both CD4 + T cells and keratinocytes gathering around the lesion. The increasing in ammatory cytokine excretion of CD4 + T cells in psoriasis was suppressed by Pri@exo. Besides, Pri@exo treatment alleviated ferroptosis-related changes in psoriatic skin, thereby dampening excessive in ammation and, in turn, decreasing the abnormal proliferation of keratinocytes in psoriatic lesions.Conclusion: This tumor-derived PD-L1 + exosomes has a natural in ammatory tropism and excellent antiin ammatory effect, and able to act as a bio-inspired nanocarrier for various therapeutic agents to optimized in ammatory disease therapy.

Pristimerin Exerts Pharmacological Effects Through Multiple Signaling Pathways: A Comprehensive Review

“…Increased pristimerin uptake with CD4+ T cells and keratinocytes, significantly inhibited the proliferation of Th17 cells, and promoted Treg differentiation in a psoriasis-like model [77] insecticidal --Exhibited marked in vitro leishmanicidal activity against promastigotes [78] Antibiosis --Caused functional alterations on the cytoplasmic membrane of S. epidermidis cells and altered the membrane permeability of S. aureus [79,80] Antiviral Human embryonic fibroblast cell line Inhibited the cytopathic effects in HCMV-infected cells and inhibited the synthesis of viral DNA but had no virucidal effect on cell-free HCMV [81] Anti-osteoporosis Ovariectomy model Inhibited the differentiation and activation of osteoclasts in vitro and in vivo [82][83][84] Ovariectomized rats Caused TRAF-6-deficient transgenic mice to suffer from osteoporosis and exhibit increased osteoclastogenesis mechanism of action of pristimerin is multi-pathway, multi-target and multi-system, which also precisely reflects the advantages of systematization, wide angle and multi-targets of Chinese medicinal preparations in disease treatment. However, there are still many unanswered questions about pristimerin, such as the specific mechanism and target are not clear, the more detailed mechanism is not explored, the common tumor types are not comprehensive, the toxic and side effects are not clear, the clinical application is seriously lacking and the bioavailability is different.In order to achieve success, future studies should focus on the following aspects: (1) to further exploring the specific mechanisms and targets of pristimerin and more detailed mechanisms through network pharmacology, molecular docking.…”

“…75 Pristimerin also inhibits the expression of endothelial adhesion molecules ICAM-1 and VCAM-1 and pro-inflammatory cytokines IL-6, IL-8, and MCP-1 induced by TNF-α-induced inhibition and acts in conjunction with the PD-L1+ exosomes to alleviate the iron-toxicityrelated changes in psoriatic skin, thereby inhibiting excessive inflammation. 76,77 Pristimerin has insecticidal properties, killing Leishmania protozoa and Trypanosoma cruzi and acting as an effective drug for Leishmaniasis and Chagas disease. 78 Pristimerin has antimicrobial properties as well, acting by altering the permeability of the plasma membranes of Staphylococcus epidermidis and Staphylococcus aureus.…”

“… 75 Pristimerin also inhibits the expression of endothelial adhesion molecules ICAM-1 and VCAM-1 and pro-inflammatory cytokines IL-6, IL-8, and MCP-1 induced by TNF-α-induced inhibition and acts in conjunction with the PD-L1+ exosomes to alleviate the iron-toxicity-related changes in psoriatic skin, thereby inhibiting excessive inflammation. 76 , 77 …”

Exosomal Proteomics: Unveiling Novel Insights into Lung Cancer

“…Furthermore, Jin et al's next-generation sequencing analysis identified specific miRNAs in EpCAM+ exosomes as biomarkers for lung adenocarcinoma and squamous cell carcinoma [68]. In addition to cancer, extensive studies have documented the unique roles of exosomal subpopulations in diseases such as neurodegenerative disorders, liver failure, osteogenesis, and retinal conditions, underscoring the critical function of exosomes in disease pathophysiology and their promise as diagnostic and therapeutic tools [69][70][71][72][73][74][75][76].…”