Exosomal microRNAs in tumor-heart crosstalk: nanobiological mechanisms and therapeutic implications.
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Exosomes are nanosized extracellular vesicles (30-200 nm) that function as natural nanocarriers for intercellular communication by transporting biological macromolecules, particularly microRNAs (miRNAs). These small, non-coding RNA macromolecules regulate gene expression post-transcriptionally and are increasingly recognized as key regulators of disease progression. Tumor-derived exosomes circulate systemically and deliver oncogenic miRNAs to distant organs, including the heart, thereby mediating long-range tumor-organ communication. Emerging evidence indicates that these exosomal miRNAs contribute to cancer-associated cardiac dysfunction independently of chemotherapy-induced cardiotoxicity. This review systematically examines the nano-biological and molecular mechanisms by which tumor-derived exosomal miRNAs particularly miR-21, miR-155, miR-34a, and miR-210 modulate apoptosis, fibrosis, inflammation, oxidative stress, and endothelial dysfunction by targeting cardioprotective proteins such as PTEN, BCL-2, and SIRT1. The efficient cellular uptake of these nanoscale vesicles by cardiomyocytes, fibroblasts, and endothelial cells triggers maladaptive remodeling, contractile dysfunction, arrhythmogenesis, and progression to heart failure. Distinct cancer types, including breast, lung, hematologic, gastrointestinal, and pediatric malignancies, release unique exosomal miRNA signatures that differentially perturb cardiovascular homeostasis. Beyond their pathogenic roles, exosomal miRNAs represent promising nano-biomarkers for minimally invasive liquid biopsy and early detection of cancer-associated cardiotoxicity. Moreover, advances in nanobiotechnology enable the development of exosome-based and miRNA-targeted therapeutic strategies, including anti-miR approaches and engineered exosome delivery systems. To our knowledge, this is the first review to integrate cancer-type and age-specific exosomal miRNA profiles with mechanistic and translational perspectives, highlighting their dual role as disease-driving macromolecules and functional cargos of nanoscale delivery systems. These insights underscore the potential of exosomal miRNAs to inform next-generation nanomedicine strategies and advance precision cardio-oncology for improved prevention and treatment of cancer-associated cardiovascular complications.