Wu Zhiye, Zeng Yinghua, Chen Huiming, Xiao Zhengnan, Guo Jingbin, Abubakar Mohamed Nor, Shen Mingzhi, Xiao Hua, Song Xudong, Cai Yanbin
Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Department of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
Department of General Practice, Hainan Hospital of Chinese PLA General Hospital, Sanya 572013, China.
ACS Appl Mater Interfaces. 2024 Sep 25;16(38):50282-50294. doi: 10.1021/acsami.4c09734. Epub 2024 Sep 13.
Heart failure (HF) represents the terminal stage of numerous cardiovascular disorders and lacks effective therapeutic strategies. The accumulation of senescent cardiomyocytes is a cardinal characteristic of HF, contributing to myocardial dysfunction and deteriorating the myocardial microenvironment through the development of senescence-associated secretory phenotypes (SASPs), ultimately culminating in pathological remodeling. Senolytics, a promising therapeutic strategy that selectively induces apoptosis in senescent cells, faces challenges due to nonspecific effects, raising concerns for clinical implementation. In this study, we developed peptide-amphiphilic nanoassemblies as responsive drug navigators for targeted delivery. The modular nanoassemblies comprise a hydrophilic domain containing a CD9-binding peptide, a hydrophobic domain incorporating a reactive oxygen species (ROS)-responsive motif, and an alkyl tail for encapsulation of the senolytic ABT263. The CD9-targeted and ROS-responsive nanoassemblies (AP@ABT263) specifically recognized senescent cardiomyocytes and modulated the release of ABT263 in the presence of elevated intracellular ROS levels. AP@ABT263 treatment significantly enhanced the targeted delivery of ABT263 to senescent cells in both in vitro and in vivo while showing minimal toxicity to normal cardiomyocytes and other tissues. Our findings provide compelling evidence that AP@ABT263 efficiently eradicated senescent cardiomyocytes, enhanced cardiac function, and attenuated the deleterious effects of SASP, thereby preventing adverse cardiac remodeling. In summary, AP@ABT263 represents a highly promising approach for responsive and controlled drug release in senescent cardiomyocytes, providing valuable insights into the development of intelligent pharmaceutical interventions for the management of HF.
心力衰竭（HF）是众多心血管疾病的终末期阶段，且缺乏有效的治疗策略。衰老心肌细胞的积累是HF的一个主要特征，它通过衰老相关分泌表型（SASP）的发展导致心肌功能障碍并使心肌微环境恶化，最终导致病理性重塑。衰老细胞溶解剂是一种有前景的治疗策略，可选择性诱导衰老细胞凋亡，但由于存在非特异性效应而面临挑战，这引发了对其临床应用的担忧。在本研究中，我们开发了肽两亲性纳米组装体作为响应性药物导航器用于靶向递送。模块化纳米组装体包括一个含有CD9结合肽的亲水区、一个包含活性氧（ROS）响应基序的疏水区以及一个用于封装衰老细胞溶解剂ABT263的烷基尾。靶向CD9且对ROS响应的纳米组装体（AP@ABT263）能特异性识别衰老心肌细胞，并在细胞内ROS水平升高时调节ABT263的释放。AP@ABT263处理在体外和体内均显著增强了ABT263向衰老细胞的靶向递送，同时对正常心肌细胞和其他组织显示出最小的毒性。我们的研究结果提供了有力证据，表明AP@ABT263能有效清除衰老心肌细胞，增强心脏功能，并减轻SASP的有害影响，从而预防不良心脏重塑。总之，AP@ABT263代表了一种在衰老心肌细胞中进行响应性和可控药物释放的极有前景的方法，为开发用于治疗HF的智能药物干预措施提供了有价值的数据。
