Abstract：
The capillarization of hepatic sinusoids resulting from the activation of hepatic stellate cells poses a significant challenge, impeding the effective delivery of therapeutic agents to the Disse space for liver fibrosis treatment. Therefore, overcoming these barriers and achieving efficient drug delivery to activated hepatic stellate cells (aHSCs) are pressing challenge. In this study, we developed a synergistic sequential drug delivery approach utilizing neutrophil membrane hybrid liposome@atorvastatin/amlisentan (NCM@AtAm) and vitamin A-neutrophil membrane hybrid liposome @albumin (VNCM@Bai) nanoparticles (NPs) to breach the capillary barrier for targeted HSC cell delivery. Initially, NCM@AtAm NPs were successfully directed to the site of hepatic fibrosis through neutrophil-mediated inflammatory targeting, resulting in the normalization of liver sinusoidal endothelial cells (LSECs) and restoration of fenestrations under the combined influence of At and Am. Elevated tissue levels of the p-Akt protein and endothelial nitric oxide synthase (eNOS) indicated the normalization of LSECs following treatment with At and Am. Subsequently, VNCM@Bai NPs traversed the restored LSEC fenestrations to access the Disse space, facilitating the delivery of Bai into aHSCs under vitamin A guidance. Lastly, both in vitro and in vivo results demonstrated the efficacy of Bai in inhibiting HSC cell activation by modulating the PPAR γ/TGF-β1 and STAT1/Smad7 signaling pathways, thereby effectively treating liver fibrosis. Overall, our designed synergistic sequential delivery system effectively overcomes the barrier imposed by LSECs, offering a promising therapeutic strategy for liver fibrosis treatment in clinical settings.
摘要：
肝星状细胞活化导致的肝窦毛细血管化构成了重大挑战，阻碍治疗剂有效递送到肝纤维化治疗的Disse空间。因此,克服这些障碍并实现向活化肝星状细胞（aHSC）的有效药物递送是紧迫的挑战。在这项研究中,我们开发了一种协同序贯药物递送方法,利用中性粒细胞膜混合脂质体@阿托伐他汀/阿利生坦(NCM@AtAm)和维生素A-中性粒细胞膜混合脂质体@白蛋白(VNCM@Bai)纳米颗粒(NPs)突破毛细血管屏障,用于靶向HSC细胞递送.最初，NCM@AtAmNP通过中性粒细胞介导的炎症靶向被成功地引导到肝纤维化部位，在At和Am的共同影响下，导致肝窦内皮细胞（LSEC）正常化并恢复开窗。p-Akt蛋白和内皮一氧化氮合酶（eNOS）的组织水平升高表明用At和Am治疗后LSEC正常化。随后，VNCM@BaiNP遍历恢复的LSEC开窗以访问Disse空间，在维生素A指导下促进Bai进入aHSC。最后,体外和体内结果都证明了Bai通过调节PPARγ/TGF-β1和STAT1/Smad7信号通路抑制HSC细胞活化的功效，从而有效治疗肝纤维化。总的来说,我们设计的协同顺序输送系统有效地克服了LSEC施加的障碍，为临床上的肝纤维化治疗提供了一个有希望的治疗策略。
