Nanomedicine guiding mitochondrial function in the treatment of cardiovascular diseases: Mechanisms, latest developments, and clinical translation.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, and ageing is their strongest biological risk factor. In the ageing cardiovascular system, mitochondrial dysfunction is not only a central driver of disease progression but also a key feature of cardiovascular ageing, linking oxidative stress, calcium dysregulation, bioenergetic failure, impaired mitochondrial dynamics, defective mitophagy, and chronic inflammation to myocardial and vascular decline. In this review, we discuss how age-associated mitochondrial alterations contribute to the pathogenesis of major CVDs and highlight their connections with broader hallmarks of ageing, including cellular senescence, proteostasis disruption, altered intercellular communication, and stem cell exhaustion. We further summarise recent advances in nanomedicine-based strategies targeting and modulating mitochondrial function, including stimulus-responsive nanocarriers, active targeting ligands, biomimetic delivery systems, and combinatorial therapeutic platforms. These approaches show promise in restoring redox balance, improving energy metabolism, limiting apoptosis, and enhancing mitochondrial quality control in conditions such as ischemia-reperfusion injury, hypertension, heart failure, and arrhythmia. Importantly, we also emphasise that ageing itself may substantially influence nanoparticle biodistribution, protein corona formation, immune recognition, intracellular trafficking, and therapeutic efficacy, thereby affecting the translational performance of mitochondrial-targeted nanomedicine in older patients. Although significant progress has been made, challenges remain in biosafety, age-relevant preclinical evaluation, manufacturing scalability, and clinical translation. We further highlight that clinical translation remains constrained by limited cardiovascular clinical evidence, patient heterogeneity, and age- and comorbidity-dependent variability in nanoparticle safety and efficacy. Overall, framing mitochondrial-targeted nanomedicine within the biology of cardiovascular ageing may provide a more precise and clinically relevant strategy for preventing and treating age-related CVDs.