Surface engineering of exosomes enhances the therapeutic efficacy of rheumatoid arthritis by macrophage reprogramming.

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Extracellular vesicles (EVs) are essential mediators in intercellular communication that have emerged as natural therapeutic nanomedicines for the treatment of intractable diseases. Their therapeutic applications, however, have been limited by unpredictable in vivo biodistribution after systemic administration. To control the in vivo fate of EVs, their surfaces should be properly edited, depending on the target site of action. Herein, based on bioorthogonal copper-free click chemistry (BCC), surface-edited EVs were prepared by using metabolically glycoengineered cells. First, the exogenous azide group was generated on the cellular surface through metabolic glycoengineering (MGE) using the precursor. Next, PEGylated hyaluronic acid, capable of binding specifically to the CD44-expressing cells, was labelled as the representative targeting moiety onto the cell surface by BCC. The surface-edited EVs effectively accumulated into the target tissues of the animal models with rheumatoid arthritis and tumour, primarily owing to prolonged circulation in the bloodstream and the active targeting mechanism. Overall, these results suggest that BCC combined with MGE is highly useful as a simple and safe approach for the surface modification of EVs to modulate their in vivo fate. K E Y WO R D S biodistribution, bioorthogonal copper-free click chemistry, CD44-targeting, extracellular vesicles, metabolic glycoengineering  INTRODUCTION Extracellular vesicles (EVs) are extracellular membrane vesicles (30-200 nm in diameter) that are endogenously released by cells and are present in most biological fluids, including blood, urine and saliva (El Andaloussi et al., 2013; Mathieu et al., 2019). Depending on the cellular origin, EVs have specific bioactive components corresponding to unique biological functions (Van Den Boorn et al., 2013). Recently, they have been identified as essential mediators in intercellular communication, transferring various biological signals between cells such as lipids, proteins, mRNAs and other noncoding RNAs (Tkach & Théry, 2016). EVmediated cellular communication is heavily implicated in normal physiological processes such as inflammation, homeostasis and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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