PDF(Pubmed)
Abstract：
Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.
摘要：
急性肝衰竭（ALF）是一种罕见且严重的疾病，其特征是主要的肝细胞死亡和肝功能障碍。由于治疗选择有限，这种疾病通常预后差，死亡率高。当ALF不能通过药物逆转时，经常需要肝移植。然而,移植排斥和供体器官短缺仍然是主要挑战。最近,干细胞疗法已成为治疗肝脏疾病的有希望的替代方法。然而,有限的细胞递送途径和不良的活细胞产品的稳定性极大地阻碍了干细胞疗法的可行性和治疗效果。受间充质干细胞（MSCs）功能的启发，主要通过分泌多种因子，我们开发了一种受MSC启发的仿生多功能纳米框架（MBN），该框架通过与亲水性或疏水性药物组合来封装MSC分泌的生长促进因子。用MBN包被红细胞（RBC）膜以增强其免疫耐受并延长其在血液中的循环时间。重要的是,MBN可以响应氧化微环境，在那里它积累和降解以释放有效载荷。在这项工作中,两种仿生纳米粒子，即,大黄酸包裹的MBN（RMBN）和N-乙酰半胱氨酸（NAC）包裹的MBN（NMBN），被设计和合成。在脂多糖（LPS）/d-半乳糖胺（D-GalN）诱导和对乙酰氨基酚（APAP）诱导的ALF小鼠模型中，RMBN和NMBN可以有效靶向肝脏病变，缓解ALF的急性症状，并通过其强大的抗氧化作用促进肝细胞再生，抗炎,和再生活动。这项研究证明了使用MSC启发的仿生纳米框架治疗ALF的可行性。
