Nanomedicine for Cardiac Repair in Heart Failure: From Targeted Delivery to Regenerative Modulation.

Heart failure is a progressive syndrome in which the heart fails to maintain adequate output and remains a leading cause of mortality and healthcare utilization despite guideline-directed pharmacological and device-based therapies. A major contributor to this residual burden is the limited myocardial specificity of conventional treatments, which act systemically and incompletely address the heterogeneous microenvironment of the failing ventricle. Nanomedicine employs nanoscale carriers to reshape pharmacokinetics, protect labile cargo, and enhance delivery to injured myocardium. Preclinical studies in predominantly heart failure with reduced ejection fraction (HFrEF) models, including post-myocardial infarction and pressure-overload injury, demonstrate that targeted nanoplatforms can improve left ventricular ejection fraction by approximately 5-15 percentage points, reduce infarct size by 20-50%, and attenuate fibrosis, inflammation, or cardiomyocyte apoptosis by 30-60% compared with control treatments. Spatially and temporally controlled delivery of small molecules, proteins, and nucleic acids is possible using organic and inorganic nanoparticles and catalytic systems, biomimetic and bioderived carriers, extracellular vesicles, and nanostructured hydrogels or patches, with some also providing mechanical support or theranostic imaging. There is limited evidence in heart failure with preserved ejection fraction (HFpEF). Early studies have focused on inflammation, fibrosis, and microvascular dysfunction rather than on contractile recovery. Importantly, the majority of nanomedicine strategies discussed remain at the preclinical stage, with clinical experience largely confined to early-phase safety and feasibility studies. This review summarizes information from in vitro systems, small- and large-animal models, and newly developed clinical studies, and critically examines translational issues such as toxicity, immunogenicity, scalability, and regulatory complexity. New approaches to cardiac regeneration, such as local delivery of pro-regenerative signals, are also supported by nanomedicine, which facilitates the delivery of pro-regenerative cues, such as regulatory RNAs and extracellular vesicles, to promote cardiomyocyte survival, angiogenesis, and limited myocardial tissue renewal.