Injured cardiac targeting magnetic nanovesicles for mRNA treatment of myocardial infarction

<b>Rationale:</b> Inflammation and myocardial remodeling are major contributors to the progression of cardiac diseases. mRNA-based therapeutics have emerged as a promising modality for cardiovascular intervention; however, their clinical translation remains constrained by challenges in achieving efficient and spatially precise delivery to diseased cardiac tissue, particularly following myocardial injury. To address this unmet need, a dual-active magnetic nanocarrier was engineered for targeted mRNA delivery to damaged cardiovascular tissue. <b>Methods:</b> The interleukin-10 anti-inflammatory cytokine mRNA (<i>IL-10</i> mRNA) was encapsulated in lipid nanoparticles, which were fused with nanovesicles derived from mesenchymal stem cells (NVs) and functionalized with cardiac-targeting peptides (T peptides) to form <i>IL-10</i> mRNA-loaded T-NVs (<i>m10</i>@T-NVs). Magnetic nanoparticles (MNPs) were conjugated with azide-modified antibodies against CD63 and myosin light chain 3 (MLC3), which are overexpressed in damaged myocardial tissue <i>via</i> click chemistry, to enable targeted delivery to injured cardiac tissue. Subsequently, the <i>m10</i>@T-NVs were combined with functionalized MNPs <i>via</i> CD63 interactions to form <i>m10</i>@T-MNVs. <b>Results:</b> <i>m10</i>@T-MNVs were developed and characterized, confirming the functionalization of NVs and MNPs. Under guided of an external magnetic field, <i>m10</i>@T-MNVs exhibited a 4.5-fold increase in accumulation in H₂O₂-induced injured cardiomyocytes and damaged cardiac regions, achieving significantly higher delivery efficiency. In a mouse model of myocardial infarction (MI), administration of <i>m10</i>@T-MNVs enhanced intramyocardial IL-10 mRNA expression and cytokine production. This led to the polarization of macrophages toward an M2 anti-inflammatory phenotype, mitigation of tissue injury, reduced apoptosis, attenuation of fibrosis, and suppression of pathological myocardial remodeling. <b>Conclusions:</b> Dual-active targeting of injured cardiac tissue using magnetic nanocarriers constitutes a promising therapeutic strategy for cardiovascular diseases by addressing key challenges associated with tissue-selective mRNA delivery in the injured myocardium.