Plant exosomes exhibit high stability and easy absorption, and have emerged as promising bioactive tools due to their potential health benefits and biomedical applications. Saffron tepals contain abundant metabolites with potential therapeutic properties and were used for exosome extraction by ultracentrifugation and gradient purification. The exosomes showed an average particle size of 151.5 ± 79.6 nm and exhibited a spherical morphology. Five well-conserved miRNAs—miR157, miR166, miR168, miR396, and miR398—were identified in the exosomes, which are involved in the coordination of growth and physiological plant responses with endogenous and environmental abiotic and biotic signals, and their potential targets in mammals are upregulated in specific cancer types and associated with inflammation. Proteome analysis revealed an enrichment of proteasome proteins, ribosomal proteins, and proteins involved in the cytoskeleton, transport across the membrane (ABC transporters), and vesicle trafficking (RAB GTPases, TM9SF and Coatomer subunits). Metabolite analyses showed mainly anthocyanins. The exosomes have selective stimulatory activity on macrophages, increasing the expression of surface molecules (CD80 and CD86), and cytokines (IL-1β, IL-6, and TNF-α), but not the levels of IL-10. Overall, these results indicated that saffron flowers are an effective and abundant source of exosomes as new nanomedicines for human health. © 2025 by the authors.; Saffron tepals constitute a rich source of bioactive metabolites, but are considered waste material after saffron processing. Herein, we obtained exosomes from this material and explored their potential for biomedical applications. Exosomes were isolated through ultracentrifugation following gradient purification, revealing an average particle size of 151.5 ± 79.6 nm with an exosome-like morphology. Detailed analysis identified five well-conserved plant miRNAs—miR157, miR166, miR168, miR396, and miR398—which are involved in regulating plant growth and responses to both biotic and abiotic stress and have potential mammalian targets that are upregulated in certain cancer types and are associated with inflammation. Proteomic analysis of the exosomes revealed an enrichment in proteasome components, ribosomal proteins, and proteins involved in cellular processes such as cytoskeletal organization, membrane transport, and vesicle trafficking. Furthermore, metabolite profiling identified anthocyanins as the predominant metabolites in the exosomes, which are known for their antioxidant properties. Functional assays demonstrated that saffron-derived exosomes selectively activate macrophages, increasing the expression of surface markers and pro-inflammatory cytokines. These findings suggest that saffron tepals are a promising and abundant source of exosomes with potential applications in nanomedicine and immune modulation for therapeutic purposes. © 2025 by the authors.

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