Targeted heart repair by Tß4-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 ß4 (Tß4) was loaded into the nanoparticles, resulting in Tß4-MmEVs. In vitro experiments indicated that both the MmEVs and Tß4-MmEVs promoted cardiomyocyte proliferation and endothelial cell migration. Animal experiments suggested that MI mice treated with MmEVs and Tß4-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: Extracellular vesicles (EVs) derived from bioactive parent cell sources involved in pathological and repair processes for cardiovascular disease have emerged as a compelling strategy for regenerative therapy. In this study, we constructed monocyte membrane-modified extracellular vesicles loaded with a drug (Tß4-MmEVs) for heart repair that exhibit extraordinary abilities of immune evasion and sequential localization to damaged regions owing to the presence of CD47 and the strong affinity between monocytes and damaged cardiomyocytes and endothelial cells. The bioactivities of Tß4-MmEVs on enhancing cardiomyocyte and endothelial cell proliferation were validated both in vitro and in vivo. Effective development and implementation of therapeutically membrane-modified nanoparticles from homologous origins can provide a reference for adjuvant therapy in clinical MI management.

A dual-targeting peptide facilitates targeting anti-inflammation to attenuate atherosclerosis in ApoE-/- mice.

We report a peptidic dual-targeting drug delivery platform (integrins targeting and self-assembly instructed by matrix metalloproteinases) towards inflamed endothelial cells, which improved the anti-inflammatory ability of the loaded drug (i.e., puerarin) in vitro and thus improved the antiatherogenic effect of the loaded drug (i.e., puerarin) in vivo.

Fabrication of Tß4-Exosome-releasing artificial stem cells for myocardial infarction therapy by improving coronary collateralization.

Currently, stem cell transplantations in cardiac repair are limited owing to disadvantages, such as immunological rejection and poor cell viability. Although direct injection of exosomes can have a curative effect similar to that of stem cell transplantation, high clearance hinders its application in clinical practice. Previous reports suggested that induction of coronary collateralization can be a desired method of adjunctive therapy for someone who had missed the optimal operation time to attenuate myocardial ischemia. In this study, to mimic the paracrine and biological activity of stem cells, we developed artificial stem cells that can continuously release Tß4-exosomes (Tß4-ASCs) by encapsulating specific exosomes within microspheres using microfluidics technology. The results show that Tß4-ASCs can greatly promote coronary collateralization in the periphery of the myocardial infarcted area, and its therapeutic effect is superior to that of directly injecting the exosomes. In addition, to better understand how it works, we demonstrated that the Tß4-ASC-derived exosomes can enhance the angiogenic capacity of coronary endothelial cells (CAECs) via the miR-17-5p/PHD3/Hif-1α pathway. In brief, as artificial stem cells, Tß4-ASCs can constantly release functional exosomes and stimulate the formation of collateral circulation after myocardial infarction, providing a feasible and alternative method for clinical revascularization.

Supramolecular Self-Assembled Nanofibers Efficiently Activate the Precursor of Hepatocyte Growth Factor for Angiogenesis in Myocardial Infarction Therapy.

The reconstruction of blood perfusion is a crucial therapeutic method to save and protect cardiac function after acute myocardial infarction (AMI). The activation of the hepatocyte growth factor precursor (pro-HGF) has a significant effect on promoting angiogenesis and antiapoptosis. The oxygen/glucose deprivation (OGD) caused by AMI could induce vascular adventitia fibroblasts to differentiate into myofibroblasts and secrete the pro-HGF. Meanwhile, the specific Met receptor of the hepatocyte growth factor (HGF) is upregulated in endothelial cells during AMI. However, the poor prognosis of AMI suggests that the pro-HGF is not effectively activated. Improving the activation efficiency of the pro-HGF may play a positive role in the treatment of AMI. Herein, we designed supramolecular nanofibers self-assembled by compound 1 (Comp.1, Nap-FFEG-IVGGYPWWMDV), which can strongly activate the pro-HGF and initiate HGF-Met signaling. Studies have proven that Comp.1 possesses a better ability to activate the pro-HGF to perform antiapoptosis and pro-angiogenesis. In vivo results have confirmed that the retention time of Comp.1 and its accumulation in the infarct area of the heart are promoted. Moreover, Comp.1 plays an effective role in promoting angiogenesis in the marginal area of AMI, reducing myocardial fibrosis, and protecting cardiac function. Herein, we will optimize the structure of bioactive peptides through supramolecular self-assembly and amplify their therapeutic effect by improving their efficiency, providing a new strategy for the therapy of AMI.