An integrated “Engage & Evasion” approach for mononuclear phagocyte system escape and efficient extracellular vesicle therapy

Ischemic diseases are major contributors to global morbidity and mortality, posing a substantial threat to human health. Extracellular vesicles (EVs) play an essential role in enhancing neovascularization in ischemic tissues, thereby facilitating tissue repair and regeneration. However, the utilization of EVs is hindered by their rapid uptake and clearance by the mononuclear phagocyte system (MPS), which markedly impedes their therapeutic efficacy and organ-specific accumulation. Notably, CD47, upon binding to signal regulatory protein alpha, initiates a "don't eat me" signal, enabling immune evasion from the MPS. Our research has demonstrated that phagocytes predominantly engulf CD47^low dendritic DC2.4 cell-derived EVs (DV), while engineered CD47^high EVs (MV⁴⁷) experience minimal ingestion. Leveraging these findings, we have developed a dual-faceted "Engage & Evasion" strategy. Initially, DVs were employed to saturate the MPS, serving as the "engage" component. Subsequently, MV⁴⁷, fortified with CD47, was introduced for "evasion" purposes. This approach effectively minimized entrapment by the liver and spleen, boosted serum concentration, and enhanced final accumulation in non-MPS organs. In summary, our "Engage & Evasion" therapeutic strategy offers a promising avenue to enhance EV therapeutic potential against ischemic challenges through improved systemic distribution.