Gao Meng, Yin Lianhong, Zhang Bo, Dong Zhichao, Jiang Wenjiao, Bai Zhuoya, Zhao Xuerong, Xu Lina, Wang Ning, Peng Jinyong
College of Pharmacy, Dalian Medical University, Dalian 116044, China.
Department of Cardiology, The First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.
ACS Nano. 2025 May 20;19(19):18475-18491. doi: 10.1021/acsnano.5c01641. Epub 2025 May 8.
Despite advancements in the development of targeted approaches for the treatment of myocardial infarction (MI), there is a continuing need for improvements in treatment approaches due to the high mortality and prevalence of MI. The identification of specific therapeutic targets and the development of efficient delivery systems are essential. In this study, a nanoparticle delivery system targeting necrotic cardiomyocytes was engineered. This system effectively downregulated long noncoding RNA (lncRNA) AK156373 and reduced oxidative stress and inflammation during MI progression. Mechanistically, silencing lncRNA AK156373 enhanced the viability and mitochondrial function of hypoxic cardiomyocytes and lowered intracellular inflammatory cytokine levels and reactive oxygen species (ROS) production. , cardiac-specific lncRNA AK15673 knockout mice were generated (AK156373 mice), and lncRNA AK156373 knockout obviously reduced the infarct size, collagen fiber deposition, and ischemia severity in MI mice, leading to improved cardiac function. Additionally, lncRNA AK156373 modulated miR-204-5p to regulate C-X-C motif chemokine receptor 2 (CXCR2) protein expression via the competing endogenous RNA (ceRNA) mechanism, exacerbating myocardial damage and accelerating MI progression. Subsequently, nanoparticles loaded with lncRNA AK156373 siRNA were synthesized. The nanoparticles significantly inhibited MI progression by modulating the miR-204-5p/CXCR2 axis to reduce oxidative stress and inflammation. Overall, these findings establish a key regulatory role for lncRNA AK156373 in MI progression and present a direct preclinical approach for MI therapy.
尽管在心肌梗死（MI）治疗的靶向方法开发方面取得了进展，但由于MI的高死亡率和高患病率，仍持续需要改进治疗方法。确定特定的治疗靶点和开发有效的递送系统至关重要。在本研究中，设计了一种靶向坏死心肌细胞的纳米颗粒递送系统。该系统有效地下调了长链非编码RNA（lncRNA）AK156373，并在MI进展过程中降低了氧化应激和炎症反应。从机制上讲，沉默lncRNA AK156373可增强缺氧心肌细胞的活力和线粒体功能，并降低细胞内炎性细胞因子水平和活性氧（ROS）生成。此外，构建了心脏特异性lncRNA AK15673基因敲除小鼠（AK156373小鼠），lncRNA AK156373基因敲除明显减小了MI小鼠的梗死面积、胶原纤维沉积和缺血严重程度，从而改善了心脏功能。此外，lncRNA AK156373通过竞争性内源RNA（ceRNA）机制调节miR-204-5p，以调控C-X-C基序趋化因子受体2（CXCR2）蛋白表达，加剧心肌损伤并加速MI进展。随后，合成了负载lncRNA AK156373 siRNA的纳米颗粒。这些纳米颗粒通过调节miR-204-5p/CXCR2轴来显著抑制MI进展，以减轻氧化应激和炎症反应。总体而言，这些发现确立了lncRNA AK156373在MI进展中的关键调控作用，并为MI治疗提供了一种直接的临床前方法。
