PDF(Pubmed)
Abstract：
Hypervascularized glioblastoma is naturally sensitive to anti-angiogenesis but suffers from low efficacy of transient vasculature normalization. In this study, a lipid-polymer nanoparticle is synthesized to execute compartmentalized Cas9 and sgRNA delivery for a permanent vasculature editing strategy by knocking out the signal transducer and activator of transcription 3 (STAT3). The phenylboronic acid branched cationic polymer is designed to condense sgRNA electrostatically (inner compartment) and patch Cas9 coordinatively (outer compartment), followed by liposomal hybridization with angiopep-2 decoration for blood-brain barrier (BBB) penetration. The lipid-polymer nanoparticles can reach glioblastoma within 2 h post intravenous administration, and hypoxia in tumor cells triggers charge-elimination and degradation of the cationic polymer for burst release of Cas9 and sgRNA, accompanied by instant Cas9 RNP assembly, yielding ≈50% STAT3 knockout. The downregulation of downstream vascular endothelial growth factor (VEGF) reprograms vasculature normalization to improve immune infiltration, collaborating with interleukin-6 (IL-6) and interleukin-10 (IL-10) reduction to develop anti-glioblastoma responses. Collectively, the combinational assembly for compartmentalized Cas9/sgRNA delivery provides a potential solution in glioblastoma therapy.
摘要：
高血管化的成胶质细胞瘤对于抗血管生成是天然敏感的,但是遭受短暂的脉管系统正常化的低功效。在这项研究中,通过敲除信号转导和转录激活因子3(STAT3),合成脂质-聚合物纳米颗粒以执行分隔的Cas9和sgRNA递送,从而实现永久性血管编辑策略.苯基硼酸支化阳离子聚合物设计用于静电凝聚sgRNA（内室）和贴片Cas9（外室），然后通过脂质体杂交与血管肽-2修饰进行血脑屏障（BBB）渗透。脂质-聚合物纳米粒可以在静脉给药后2小时内到达胶质母细胞瘤，和缺氧在肿瘤细胞触发电荷消除和降解的阳离子聚合物的爆发释放的Cas9和sgRNA，伴随着即时Cas9RNP组装，产量≈50%STAT3敲除。下游血管内皮生长因子（VEGF）的下调重新编程血管正常化，以改善免疫浸润，与白细胞介素-6（IL-6）和白细胞介素-10（IL-10）减少合作以产生抗胶质母细胞瘤反应。总的来说，用于分隔Cas9/sgRNA递送的组合组装为胶质母细胞瘤治疗提供了潜在的解决方案。
