Synergistic therapy on myocardial infarction via a monocyte-driven non-cell-autonomous system. Mus musculus

Myocardial infarction therapy remains a significant challenge in managing cardiomyocyte loss and inflammation-induced fibrosis hyperplasia, which causes considerable morbidity and mortality. Recently, cell-based therapy provided opportunities to restore the lost cardiomyocytes via exogenous implantation in a cell-autonomous manner. However, pernicious microenvironments and overactivation of inflammatory cells prohibit tissue regeneration and cardiomyocyte survival. Here, we demonstrate a synergistic strategy for myocardial infarction treatment through a monocyte-driven non-cell-autonomous system (namely MoNa system), which allows modified microenvironment inflammation and triggers cardiomyocyte proliferation by controlled release of therapeutics on the monocyte surface. The facial-constructed MoNa system showed a 10-fold higher heart-liver ratio of targeting accumulation compared to a free therapeutic treatment. Notably, the substantial accumulation of therapeutics reverses a pro-inflammatory environment and stimulates the regeneration of surviving cardiomyocytes, showing significant potential in MI synergistic therapy. Consequently, the cardiac functions in the MI mice model treated with this MoNa system improved enormously (~2.5 fold higher) compared with free therapeutics.

心肌梗死（myocardial infarction）治疗仍是应对心肌细胞丢失与炎症诱导纤维化增生的重大临床挑战，此类病理进程可引发极高的发病率与死亡率。近年来，细胞治疗（cell-based therapy）为通过细胞自主方式外源性植入以修复丢失的心肌细胞提供了全新途径。然而，有害微环境与炎症细胞过度激活会抑制组织再生与心肌细胞存活。本研究提出一种基于单核细胞（monocyte）驱动的非细胞自主系统（下称MoNa系统）的心肌梗死协同治疗策略，该系统可通过单核细胞表面治疗剂的可控释放，调节微环境炎症状态并触发心肌细胞增殖。与游离治疗剂给药组相比，该表面构建的MoNa系统的靶向蓄积心肝比提升了10倍。值得注意的是，治疗剂的大量蓄积可逆转促炎微环境，促进存活心肌细胞的再生，在心肌梗死协同治疗中展现出显著应用潜力。综上，与游离治疗剂组相比，接受MoNa系统治疗的心肌梗死小鼠模型的心脏功能得到显著改善（提升约2.5倍）。