Lin Yanxia, Liu Jianfeng, Bai Rui, Shi Jinmiao, Zhu Xiaoming, Liu Jian, Guo Jing, Zhang Wei, Liu Huiliang, Liu Zhiqiang
Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China.
Department of Cardiology, The Third Medical Center of PLA General Hospital, Beijing 100039, China.
ACS Nano. 2020 Sep 22;14(9):11846-11859. doi: 10.1021/acsnano.0c04727. Epub 2020 Sep 9.
Stimuli-responsive nanoparticles (NPs), so-called "smart" NPs, possess great potentials in drug delivery. Presently, the intelligence of smart NPs is mainly based on their chemical or physical changes to stimuli, which are usually "mechanical" and fundamentally different from biological intelligence. Inspired by mitochondria (MT), a biosmart nanoparticle with microenvironment targeting and self-adaptive capacity (MTSNP) was fabricated for ischemic tissue repair. The nanoparticles were designed as shell@circular DNA@shell@core. The double shells were like the two-layered membranes of MT, the melatonin-loaded cores corresponded to the MT matrix, and the circular DNA corresponded to MTDNA. In function, melatonin-loaded cores simulated the cell-protective mechanism of MT, which naturally synthesized melatonin to resist ischemia, while circular DNA was constructed to mimic the biological oxygen-sensing mechanism, synthesizing VEGF for vascularization according to oxygen level, like the ATP supply by MT according to microenvironment demand. At the acute stage of ischemia, melatonin was rapidly released from MTSNP to scavenge reactive oxygen species and activated melatonin receptor I on MT to prevent cytochrome release, which would activate apoptosis. During the chronic stage, circular DNA could sense hypoxia and actively secrete VEGF for revascularization as a response. Importantly, circular DNA could also receive feedback of revascularization and shut down VEGF secretion as an adverse response. Then, the therapeutic potentials of the MTSNP were verified in myocardial ischemia by the multimodality of the methods. Such nanoparticles may represent a promising intelligent nanodrug system.
刺激响应性纳米颗粒（NPs），即所谓的“智能” NPs，在药物递送方面具有巨大潜力。目前，智能 NPs 的智能性主要基于它们对刺激的化学或物理变化，这些变化通常是“机械性的”，与生物智能有根本区别。受线粒体（MT）启发，制备了一种具有微环境靶向和自适应能力的生物智能纳米颗粒（MTSNP）用于缺血组织修复。纳米颗粒被设计为壳@环状 DNA@壳@核结构。双层壳类似于 MT 的两层膜，负载褪黑素的核对应于 MT 基质，环状 DNA 对应于线粒体 DNA（MTDNA）。在功能上，负载褪黑素的核模拟了 MT 的细胞保护机制，MT 天然合成褪黑素以抵抗缺血，而环状 DNA 的构建是为了模拟生物氧传感机制，根据氧水平合成血管内皮生长因子（VEGF）以促进血管生成，就像 MT 根据微环境需求供应三磷酸腺苷（ATP）一样。在缺血急性期，褪黑素从 MTSNP 中快速释放以清除活性氧，并激活 MT 上的褪黑素受体 I 以防止细胞色素释放，否则会激活细胞凋亡。在慢性期，环状 DNA 可感知缺氧并作为反应主动分泌 VEGF 以促进血管再生。重要的是，环状 DNA 还可接收血管再生的反馈并作为不良反应关闭 VEGF 分泌。然后，通过多种方法验证了 MTSNP 在心肌缺血中的治疗潜力。这类纳米颗粒可能代表一种有前景的智能纳米药物系统。
