The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University or The First School of Clinical Medicine, Southern Medical University, Dongguan 523018, China.
Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
ACS Nano. 2023 Dec 26;17(24):24773-24789. doi: 10.1021/acsnano.3c05261. Epub 2023 Dec 6.
As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. , the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.
随着血管钙化 (VC) 的患病率不断增加，其已成为心血管发病率和死亡率的主要因素，因此对治疗药物的需求变得尤为迫切。硫代硫酸钠 (STS) 是一种已被临床批准用于治疗 VC 的药物，但由于其生物利用度差和严重的不良反应，其疗效受到限制。植物来源的细胞外囊泡为 VC 治疗提供了选择，因为它们可用作仿生药物载体，具有比人工载体更高的生物安全性和靶向能力。受天然葡萄柚来源细胞外囊泡 (EVs) 的启发，我们构建了一种仿生纳米载体，该载体由负载 STS 的 EVs 组成，并进一步用羟基磷灰石晶体结合肽 (ESTP) 进行修饰，以实现 STS 对 VC 的靶向递送。结果表明，ESTP 纳米药物对钙化血管平滑肌细胞 (VSMCs) 具有优异的细胞摄取能力，并能抑制 VSMCs 钙化。在 VC 小鼠模型中，与其他治疗组相比，ESTP 纳米药物在钙化动脉中表现出最高的优先蓄积。机制上，ESTP 纳米药物通过驱动 M2 巨噬细胞极化、减少炎症以及抑制骨血管轴来显著预防 VC，具体表现为抑制 VSMCs 的成骨表型转分化，同时增强骨质量。此外，ESTP 纳米药物不会引起溶血或对其他器官造成任何损害。这些结果表明，ESTP 纳米药物有望成为一种治疗 VC 的新型药物，而不会引起全身毒性的担忧。
