Introduction: Mesenchymal stem cells (MSCs) are a natural source of extracellular vesicles (EVs) with significant potential for therapeutic applications in immunomodulation. The engineering of MSC-derived EVs as targeted drug delivery systems represents an innovative approach for addressing inflammatory diseases. In this study, we explored a bioengineering-based strategy to enhance the therapeutic efficacy of MSC-derived EVs (MSC-EVs) through the incorporation of dexamethasone (Dex), a potent anti-inflammatory corticosteroid.

Methods: Three distinct drug delivery formulations were designed: EVs isolated from Dex-preconditioned MSCs (Pre-Dex-EVs), EVs loaded with Dex post-isolation (L-Dex-EVs), and the co-administration of free Dex with unmodified EVs (Dex + EVs). The integrity and morphology of the vesicles were confirmed both before and after drug loading. Subsequently, each formulation was evaluated for its capacity to modulate macrophage polarization in a lipopolysaccharide (LPS)-induced inflammatory model.

Results: All EV-based strategies significantly reduced M1-associated genes (iNOS, IRF5, Stat1), cytokines (TNF-α, IL6), and surface markers (CD86), while concurrently enhancing M2-related markers (Arg-1, IRF4, Stat6), IL10 secretion, and CD206 expression. Notably, L-Dex-EVs exhibited superior delivery efficiency and more potent immunomodulatory effects, demonstrating the impact of EV engineering on therapeutic outcomes.

Conclusion: These findings emphasize the role of bioengineered MSC-derived EVs as next-generation drug delivery vehicles, offering a versatile and safer platform for targeted immunotherapy with reduced systemic toxicity.