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.

Injectable photocurable Janus hydrogel delivering hiPSC cardiomyocyte-derived exosome for post-heart surgery adhesion reduction.

Postsurgical pericardial adhesions pose increased risks of sequelae, prolonged reoperation time, and reduced visibility in the surgical field. Here, we introduce an injectable Janus hydrogel, which exhibits asymmetric adhesiveness properties after photocrosslinking, sustained delivering induced pluripotent stem cell-derived cardiomyocyte exosomes (iCM-EXOs) for post-heart surgery adhesion reduction. Our findings reveal that iCM-EXOs effectively attenuate oxidative stress in hydrogen peroxide-treated primary cardiomyocytes by inhibiting the activation of the transcription factor nuclear factor erythroid 2-related factor 2. Notably, in rat cardiac postsurgery models, the Janus hydrogels loaded with iCM-EXOs demonstrate dual functionality, acting as antioxidants and antipericardial adhesion agents. These hydrogels effectively protect iCM-EXOs from GATA6+ cavity macrophage clearance by inhibiting the recruitment of macrophages from the thoracic cavity. These results highlight the promising potential of iCM-EXO-laden Janus hydrogels for clinical safety and efficacy validation in trials involving heart surgery patients, with the ultimate goal of routine administration during open-heart surgeries.

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.

A novel five-gene signature predicts overall survival of patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common public health challenges, worldwide. Because of molecular complexity and tumor heterogeneity, there are no effective predictive models for prognosis of HCC. This underlines the unmet need for accurate prognostic models for HCC. Analysis of GSE14520 data from gene omnibus (GEO) database identified multiple differentially expressed mRNAs (DEMs) between HCC and normal tissues. After randomly stratifying the patients into the training and testing groups, we performed univariate, lasso, and multivariable Cox regression analyses to delineate the prognostic gene signature in training set. We then used Kaplan-Meier plot, time-dependent receiver operating characteristic (ROC), multivariable Cox regression analysis of clinical information, nomogram, and decision curve analysis (DCA) to evaluate the predictive and overall survival value of a novel five-gene signature (CNIH4, SOX4, SPP1, SORBS2, and CCL19) within and across sets, separately and combined. We also validated the prognostic value of the five-gene signature using The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC), GSE54236 and International Cancer Genome Consortium (ICGC) sets. Multivariable Cox regression analysis revealed that the five-gene signature and tumor node metastasis (TNM) stage were independent prognostic factors for overall survival of HCC patients in GSE14520 and TCGA-LIHC. Combining TNM stage clinical pathological parameters and nomogram greatly improved the prognosis prediction of HCC. Further gene set enrichment analysis (GSEA) revealed enrichment of KEGG pathways related to cell cycle in the high-risk group and histidine metabolism in the low-risk group. Finally, all these five mRNAs are overexpressed between 12 pairs of HCC and adjacent normal tissues by quantitative real-time PCR validation. In brief, a five-gene prognostic signature and a nomogram were identified and constructed, respectively, and further validated for their HCC prognostic value. The five-gene risk score together with TNM stage models could aid in rationalizing customized therapies in HCC patients.