Conclusion
hEV@FAP represents a novel approach for targeted delivery of therapeutic siRNA to injured cardiac tissues, providing a promising nanomedicine for cardiac repair.
Methods
To identify fibroblast activation protein (FAP) as a potential target for delivery to injured cardiac tissue, we analyzed cardiac tissues from patients with heart failure and angiotensin II (Ang II)-treated mice. Injured cardiac tissue-targeting EVs were developed by embedding a cholesterol-conjugated FAP aptamer, which specifically targets FAP, onto human serum-derived EVs (hEV).
Purpose
Small-interfering RNA (siRNA) therapy holds significant potential for treating cardiac injury; however, its clinical application is constrained by poor blood stability and insufficient cellular uptake. Extracellular vesicles (EVs) have emerged as an effective delivery system for siRNA in vivo; but their lack of specific cell or tissue-targeting ability remains a major challenge. Thus, we aimed to develop an EV-based delivery system capable of targeted delivery of therapeutic siRNA to injured cardiac tissue for cardiac repair.
Results
Our findings revealed that FAP is upregulated after cardiac injury, highlighting its potential as a target for siRNA delivery to injured cardiac tissues. We successfully developed FAP aptamer-functionalized hEV (hEV@FAP) and confirmed their typical EV characteristics, including morphology, size distribution, zeta potential, and marker protein expression. In addition, hEV@FAP demonstrated high targeting selectivity to FAP-positive regions both in vitro and in vivo. To treat cardiac injury, hEV@FAP were loaded with TGFβ1 siRNA (siTGFβ1), identified as a molecular target for cardiac repair. In Ang II-treated mice, intravenous administration of hEV@FAP-siTGFβ1 effectively reduced Ang II-induced TGFβ1 expression in cardiac tissues, attributed to the protective and targeting capabilities of hEV@FAP. Consequently, hEV@FAP-siTGFβ1 significantly improved cardiac function, reduced myocardial fibrosis, and decreased cardiomyocyte cross-sectional area (P < 0.05) without inducing systemic toxicity.