Abstract Background Inflammation and myocardial remodeling are key contributors to the progression of cardiovascular diseases. Although mRNA-based therapies hold great potential for treating cardiovascular diseases, the lack of efficient and targeted delivery systems limits their therapeutic application, particularly in injured cardiac tissue. Objectives This study aims to develop a dual-active magnetic nanocarrier for precise mRNA therapy, enabling targeted IL-10 mRNA delivery to injure cardiac tissue while enhancing therapeutic efficacy through injury-specific accumulation and anti-inflammatory response. Methods A dual-active magnetic nanocarrier functionalized with cardiac-targeting peptide (CTP) and myosin light chain 3 (MLC3) antibodies and for targeted mRNA delivery to injured cardiovascular tissue. To achieve targeted delivery, magnetic nanoparticles (Mag) were conjugated azide-functionalized anti-CD63 and anti-MLC3, a protein overexpressed in damaged myocardial tissue antibodies via click chemistry. Anti-inflammatory cytokine IL-10 mRNA (m10) encapsulated in lipid nanoparticles, which were fused with mesenchymal stem cell-derived nanovesicles (NVs), and modified with CTPs to form IL-10 mRNA loaded CTP-NVs (m10-CTP-NVs). Then, the m10-CTP-NVs were combined with functionalized Mags through CD63 interactions, forming m10-CTP-MagNVs. Results The m10-CTP-MagNVs were successfully developed and characterized, confirming their physicochemical properties, surface functionalization, and stability. The efficient mRNA delivery and functionality of the system were validated by assessing IL-10 mRNA expression in conditioned media from 10-CTP-MagNVs-treated cells. Guided by an external magnetic field, the m10-CTP-MagNVs demonstrated a 4.5-fold increase in accumulation in the H₂O₂-induced injured cardiomyocytes and damaged cardiac tissue, achieving significantly higher delivery efficiency. The m10-CTP-MagNVs induced a 6.5-fold increase in IL-10 mRNA expression (p 0.001) and robust IL-10 cytokine production in the MI mouse model. This led to the polarization of macrophages toward the M2 anti-inflammatory phenotype, as evidenced by increased expression of M2 anti-inflammatory markers. This immune modulation resulted in reduced apoptosis, as evidenced by AnnexinV/PI and TUNEL staining, along with improved preservation of cardiac architecture and function. Echocardiography showed a significant reduction in infarct size by 25% (p 0.01) and, fractional shortening. The m10-CTP-MagNVs reduced apoptosis, mitigated tissue damage, and prevented myocardial remodeling. Conclusion The dual-active injured cardiac targeting of magnetic nanocarriers represents a promising therapeutic strategy for cardiovascular diseases, addressing key challenges in injured tissue-specific mRNA therapy.
Mun et al. (Sat,) studied this question.
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