A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin.
A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin.
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DOI：
10.1016/j.biotechadv.2015.05.005
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发表时间：
2015-11-01
影响因子：
16
通讯作者：
Wickline SA
中科院分区：
文献类型：
--
作者：
Hou KK;Pan H;Schlesinger PH;Wickline SA
siRNA有可能通过使参与疾病发病机制的蛋白质高度特异性和有效沉默来彻底改变医学。尽管近20年的研究致力于将siRNA从研究工具转化为临床相关的治疗方法，但迄今为止取得的成功微乎其微。进入位于细胞质中的RNA干扰机制经常被忽视，但在设计下一代siRNA递送策略时必须考虑。肽转导结构域（PTD）已经证明了适度的siRNA转染，其主要受到内体截留的限制。旨在克服与肽载体相关的内体截留的策略在这里进行了综述，包括渗透方法，脂质缀合和融合肽。作为传统PTD的替代品，溶血肽蜂毒肽表现出内体破坏的天然能力，但引起细胞毒性。然而，适当包装和保护蜂毒肽并在内体隔室中活化和释放，使得基于蜂毒肽的策略能够证明体外和体内安全性和有效性。这些数据表明，蜂毒肽的膜破坏特性可以实现安全有效的内体溶解，为蜂毒肽作为新一代siRNA治疗剂中的关键组分建立了案例。
siRNA has the possibility to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 20 years of research dedicated to translating siRNA from a research tool into a clinically relevant therapeutic, minimal success has been had to date. Access to RNA interference machinery located in the cytoplasm is often overlooked, but must be considered when designing the next generation of siRNA delivery strategies. Peptide transduction domains (PTD) have demonstrated moderate siRNA transfection, which is primarily limited by endosomal entrapment. Strategies aimed at overcoming endosomal entrapment associated with peptide vectors are reviewed here, including osmotic methods, lipid conjugation, and fusogenic peptides. As an alternative to traditional PTD, the hemolytic peptide melittin exhibits the native capacity for endosomal disruption but causes cytotoxicity. However, appropriate packaging and protection of melittin with activation and release in the endosomal compartment has allowed melittin-based strategies to demonstrate both in vitro and in vivo safety and efficacy. These data suggest that melittin's membrane disruptive properties can enable safe and effective endosomolysis, building a case for melittin as a key component in a new generation of siRNA therapeutics.