Targeted heart repair by Tβ4-loaded cardiac-resident macrophage-derived extracellular vesicles modified with monocyte membranes.

Recent studies have demonstrated the critical role of cardiac-resident macrophages (cMacs) in the maintenance of physiological homeostasis. However, recruitment of circulating monocyte-derived macrophages decreases cMac levels post-myocardial infarction (MI). Transplanting cMacs is not an ideal option due to their low survival rates and the risk of immunological rejection. However, extracellular vesicle therapy has the potential to provide a feasible and safe alternative for cardiac repair. In this study, cell membrane-modified extracellular vesicles (MmEVs) were developed for heart repair by modifying cMac-derived extracellular vesicles (mEVs) with monocyte membranes, resulting in immune evasion and sequential targeted localization to damaged regions through expression of CD47 on MmEVs and strong affinity between monocyte membrane proteins and CCL2. Additionally, to fully exploit the potential clinical application of MmEVs and achieve a better curative effect, thymosin β4 (Tβ4) was loaded into the nanoparticles, resulting in Tβ4-MmEVs. In vitro experiments indicated that both the MmEVs and Tβ4-MmEVs promoted cardiomyocyte proliferation and endothelial cell migration. Animal experiments suggested that MI mice treated with MmEVs and Tβ4-MmEVs exhibited reduced myocardial fibrosis and increased vascular density compared to the control group. Thus, we posit that these targeted nanoparticles hold significant potential for MI adjuvant therapy and may open new avenues for cardiac repair and regeneration. STATEMENT OF SIGNIFICANCE: Nowadays, extracellular vesicles derived from the bioactive parent cell source that involve the pathological and repair process of various cardiovascular diseases have emerged as a compelling strategy for regenerative therapy. In this work, we constructed biomimetic nanoparticles (Tβ4-MmEVs) for heart repair, which exhibit extraordinary abilities of immune evasion and sequential localization to damaged regions due to the presence of CD47 expressed by mEVs and the strong affinity between monocyte membrane proteins and CCL2. Tβ4-MmEVs' bioactivities in strengthening cardiomyocyte and endothelial cell proliferation have been validated in vitro and in vivo tests. Therefore, the effective development and implementation of therapeutic biomimetic nanoparticles originating from homologous origin will give some reference value for adjuvant therapy in clinical MI management.