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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. 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 (Tβ4-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 Tβ4-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. [Display omitted] [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is one major cause of death worldwide. Safe and effective fixation of a functional cardiac patch onto the wet and dynamic myocardium is desired for clinical cardiac repair. Here, we engineered a biodegradable, conductive, and wet-adhesive hydrogel-based cardiac patch, formed by integrating polyphenol-derived redox-active and conductive nanoparticles within a flexible gelatin network. The hydrogel can directly adhere to the infarct area without eliciting a foreign body response. The hydrogel is highly flexible and mechanically resilient to accommodate the diastolic and systolic movements of the myocardium. More importantly, the hydrogel not only works as a structurally and electrically sound bridge to produce effective electrical pulses and synchronize orderly beating in cardiomyocytes but also has an immunomodulatory ability to resolve the early inflammatory response and limit ventricular remodeling. Consequently, the hydrogel simultaneously targets anti-inflammation and calcium homeostasis pathways to mediate cardiac function in both rats and minipigs following MI, which is promising for its translation into clinical practice. [Display omitted] • A biodegradable, conductive, and self-adhesive hydrogel-based cardiac patch which was composed of conductive polydopamine-hybridized poly nanoparticles (PPEDOT NPs) and a polyphenol-complexed-gelatin methacryloyl network. • PPEDOT NPs created dynamic catechol redox system, endowing the hydrogel with long-lasting adhesiveness and high conductivity. • The hydrogel simultaneously targets anti-inflammation and calcium homeostasis pathways to improve cardiac function in both rats and minipigs post-MI. [ABSTRACT FROM AUTHOR]

Cell therapy offers a promising paradigm for heart tissue regeneration. Human induced pluripotent stem cells (hiPS) and their cardiac derivatives are emerging as a novel treatment for post-myocardial infarction repair. However, the immature phenotype and function of hiPS-derived cardiomyocytes (hiPS-CMs), particularly poor electrical coupling, limit their potential as a therapy. Herein, we developed a hybrid gold nanoparticle (AuNP)-hyaluronic acid (HA) hydrogel matrix encapsulating hiPS-CMs to overcome this limitation. Methacrylate-modified-HA was used as the backbone and crosslinked with a matrix metalloproteinase-2 (MMP-2) degradable peptide to obtain a MMP-2-responsive hydrogel; RGD peptide was introduced as an adhesion point to enhance biocompatibility; AuNPs were incorporated to regulate the mechanical and topological properties of the matrix by significantly increasing its stiffness and surface roughness, thereby accelerating gap junction formation in hiPS-CMs and orchestrating calcium handling via the α n β1integrin-mediated ILK-1/p-AKT/GATA4 pathway. Transplanted AuNP-HA-hydrogel-encapsulated-hiPS-CMs developed more robust gap junctions in the infarcted mice heart and resynchronized electrical conduction of the ventricle post-myocardial infarction. The hiPS-CMs delivered by the hydrogels exerted stronger angiogenic effects, which also contributed to the recovery process. This study provides insight into constructing an injectable biomimetic for structural and functional renovation of the injured heart. [ABSTRACT FROM AUTHOR]