Transdermal psoriasis treatment inspired by tumor microenvironment-mediated immunomodulation and advanced by exosomal engineering.

Psoriasis, characterized by aberrant T cell activation and epidermal hyperplasia, lacks safe and effective localized transdermal treatments. Drawing on the divergent pathologies of psoriasis and malignancies, we explored whether immunosuppressive mechanisms from the tumor microenvironment could be repurposed for psoriasis therapy. Utilizing B16-F10 melanoma cells as a model, we found that topical application of inactivated melanoma tissue homogenate alleviated psoriatic lesions in mice, primarily mediated by melanoma-derived exosomes. These exosomes exert therapeutic effects by modulating IL-17 signaling through miRNAs, effectively reducing T cell activation and proliferation. We discovered key miRNAs, mmu-miR-320-3p and mmu-miR-126-5p, that target IL-17a. Additionally, we demonstrated that these exosomes, enriched with RhoA protein, enhance transcytosis across epidermal barriers. Based on these insights, we developed 'ExoLipo,' a biomimetic exosomal formulation incorporating RhoA and loaded with mmu-miR-320-3p, inheriting the native exosomes' transdermal and immunomodulatory capacities. This formulation exhibited significant preventive and therapeutic effects on psoriasis mice models with an excellent safety profile. Our findings highlight the potential of repurposing tumor-derived immunosuppressive strategies for inflammatory diseases and offer a groundbreaking approach for managing psoriasis.