Exosome-mimicking nanovesicles derived from efficacy-potentiated stem cell membrane and secretome for regeneration of injured tissue

Translation of exosome-based therapies to pharmaceutical use is hindered by difficulties in large-scale and cost-effective production of clinical-grade exosomes. The rational design of nanovesicles that mimic the functionalities and physicochemical properties of exosomes may circumvent these issues. In this study, membranes and secretome from efficacy-potentiated mesenchymal stem cells (MSCs) were developed into size-controllable nanovesicles (Meseomes). MSCs were primed with interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα), harvested, and exosome-mimicking Meseomes were subsequently synthesized via one-step extrusion. Meseomes demonstrated significant enhancement of pro-angiogenic, pro-proliferative, antiinflammatory, and anti-fibrotic effects on endothelial cells, macrophages, and hepatic stellate cells in vitro. Meseomes from primed MSCs benefited from an enrichment of bioactive and therapeutic molecules compared to nanovesicles from unprimed MSCs, as validated by liquid chromatography-mass spectrometry (LC-MS) proteomic analysis. Systemic administration of Meseomes to acute liver injury models resulted in the recovery of liver function, attenuated tissue necrosis. Further assessment of locally administered Meseomes in acute hindlimb ischemia models resulted in the salvage of the majority of the ischemic hindlimb (> 80%), which was due to enhanced angiogenesis and M2 macrophage polarization. The versatility and therapeutic efficacy of our developed acellular Meseomes offer an appealing alternative to traditional cell or exosome therapies for regenerative and translational medicine.