Maximizing small RNA delivery with signaling pepitdes

 描述(申请人提供)：这项以机理为基础的研究的目标是设计安全和高效的蛋白质颗粒纳米载体(PPC)用于小RNA的传递。为了实现这一点，我们计划利用细胞内的转运机制，将小RNA的传递引导到它们的作用部位，同时最大化小RNA的传递。小RNA被用于一系列健康应用中。然而，他们的潜力尚未完全发挥出来。这在很大程度上是由于传递效率低下：只有1-2%的小RNA到达RNA诱导的沉默复合体(RISC)：使用传统技术的作用部位。小RNA的传递是一个多步骤的过程，在这个过程中，任何阶段的低效都会影响基因沉默的效果。特别是，合成载体在细胞内的命运没有得到很好的了解，对TU的控制也很差。最近的研究表明，活性RISCs在功能和物理上都与MVB偶联，并不像以前认为的那样在细胞质中游离。因此，我们假设，通过主动靶向MVB，可以显著提高小RNA传递的效果。我们建议设计一种含有信号部分的PPC，这些信号部分可被细胞分选机制识别，并充当直接将小RNA运输到RISC的“分子邮政编码”。这最终可能导致增强的基因沉默。这一战略可以通过允许使用较低剂量的治疗药物来改进基于RNA的治疗，从而减少副作用并改善安全性。

 DESCRIPTION (provided by applicant): The objective of this mechanism-based research is to devise safe and efficient protein particulate nanocarriers (PPC) for small RNA delivery. To accomplish this, we plan to exploit the intracellular trafficking machinery to direct the delivery f small RNAs to their site of action while maximizing small RNA delivery. Small RNAs are used in a range of health applications. However, their potential has yet to be fully realized. This is largely due to inefficient delivery: only 1-2% of small RNAs reach the RNA-induced silencing complex (RISC): the site of action using conventional techniques. Small RNA delivery is a multistep process in which inefficiencies at any stage can compromise the efficacy of gene silencing. In particular, the intracellular fate of synthetic carriers is not well understood and tus poorly controlled. Recent studies indicate that active RISCs are functionally and physically coupled to MVBs and are not free in the cytoplasm as previously thought. Thus, we hypothesize that the effect of small RNA delivery can be significantly increased by actively targeting MVBs. We propose the design of PPCs containing signaling moieties that are recognized by the cell sorting machinery and that serve as "molecular zip codes" for the directed transport of small RNAs to the RISC. This could ultimately lead to enhanced gene silencing. This strategy could improve RNA-based therapy by allowing for the administration of lower doses of therapeutics, thereby reducing side effects and improving safety profiles.