生物工程过表达 CXCR4 的细胞膜功能化 ROS 响应性纳米治疗剂，用于靶向脑缺血再灌注损伤。

As a potentially life-threatening disorder, cerebral ischemia-reperfusion (I/R) injury is associated with significantly high mortality, especially the irreversible brain tissue damage associated with increased reactive oxygen radical production and excessive inflammation. Currently, the insufficiency of targeted drug delivery and "on-demand" drug release remain the greatest challenges for cerebral I/R injury therapy. Bioengineered cell membrane-based nanotherapeutics mimic and enhance natural membrane functions and represent a potentially promising approach, relying on selective interactions between receptors and chemokines and increase nanomedicine delivery efficiency into the target tissues. We employed a systematic method to synthesize biomimetic smart nanoparticles. The CXCR4-overexpressing primary mouse thoracic aorta endothelial cell (PMTAEC) membranes and RAPA@HOP were extruded through a 200 nm polycarbonate porous membrane using a mini-extruder to harvest the RAPA@BMHOP. The bioengineered CXCR4-overexpressing cell membrane-functionalized ROS-responsive nanotherapeutics, loaded with rapamycin (RAPA), were fabricated to enhance the targeted delivery to lesions with pathological overexpression of SDF-1. RAPA@BMHOP exhibited a three-fold higher rate of target delivery efficacy via the CXCR4/SDF-1 axis than its non-targeting counterpart in an model. Additionally, in response to the excessive pathological ROS, nanotherapeutics could be degraded to promote "on-demand" cargo release and balance the ROS level by -hydroxy-benzyl alcohol degradation, thereby scavenging excessive ROS and suppressing the free radical-induced focal damage and local inflammation. Also, the stealth effect of cell membrane coating functionalization on the surface resulted in extended circulation time and high stability of nanoparticles. The biomimetic smart nanotherapeutics with active targeting, developed in this study, significantly improved the therapeutic efficacy and biosafety profiles. Thus, these nanoparticles could be a candidate for efficient therapy of cerebral I/R injury.

作为一种潜在危及生命的疾病，脑缺血再灌注（I/R）损伤与高死亡率密切相关，尤其是与活性氧自由基产生增加和过度炎症相关的不可逆转的脑组织损伤。目前，靶向药物输送和“按需”药物释放的不足仍然是脑 I/R 损伤治疗的最大挑战。基于细胞膜的仿生纳米治疗剂模拟并增强了天然细胞膜的功能，是一种很有前途的方法，它依赖于受体和趋化因子之间的选择性相互作用，并增加纳米药物向目标组织的输送效率。

我们采用系统的方法合成了仿生智能纳米颗粒。CXCR4 过表达的原代小鼠胸主动脉内皮细胞（PMTAEC）膜和 RAPA@HOP 通过迷你挤出机在 200nm 聚碳酸酯多孔膜中挤出，以收获 RAPA@BMHOP。构建了生物工程化的 CXCR4 过表达细胞膜功能化的 ROS 响应型纳米治疗剂，负载雷帕霉素（RAPA），以增强对 SDF-1 过表达病变的靶向递送。RAPA@BMHOP 通过 CXCR4/SDF-1 轴的靶向递送效率比其非靶向对照物高 3 倍。此外，纳米治疗剂在响应过度病理 ROS 时，可以降解以促进“按需”货物释放，并通过 - 羟基苄醇降解平衡 ROS 水平，从而清除过多的 ROS 并抑制自由基诱导的局部损伤和局部炎症。此外，细胞膜涂层功能化的隐身效应导致纳米粒子的循环时间延长和稳定性提高。

本研究开发的具有主动靶向的仿生智能纳米治疗剂显著提高了治疗效果和生物安全性。因此，这些纳米粒子可能是治疗脑 I/R 损伤的有效候选药物。