Small interfering RNA (siRNA)-based RNA interference has emerged as a promising therapeutic strategy for the treatment of a wide range of?incurable diseases. However, the safe and effective delivery of siRNA therapeutics into the interior of target cells remains challenging. Here, we disclosed novel amphiphilic peptide dendrimers (AmPDs) that composed of hydrophobic two lipid-like alkyl chains and hydrophilic poly(lysine) dendrons with different generations (2C 18 -KK 2 and 2C 18 -KK 2 K 4 ) as nanovehicles for siRNA delivery. These AmPDs are able to self-assemble into supramolecular nanoassemblies that are capable of entrapping siRNA molecules into nanoparticles to protect siRNA from enzymatic degradation and promote efficient intracellular uptake without evident toxicity. Interestingly, by virtue of the optimal balance of hydrophobic lipid-like entity and hydrophilic poly(lysine) dendron generations, AmPD 2C 18 -KK 2 K 4 bearing bigger hydrophilic dendron can package siRNA to form stable, but more ready to disassemble complexes, thereby resulting in more efficient siRNA releasing and better gene silencing effect in comparison with AmPD 2C 18 -KK 2 bearing smaller dendron. Additional studies confirmed that 2C 18 -KK 2 K 4 can capitalize on the advantages of lipid and peptide dendrimer vectors for effective siRNA delivery. Collectively, our AmPD-based nanocarriers indeed represent a safe and effective siRNA delivery system. Our findings also provide a new perspective on the modulation of self-assembly amphiphilic peptide dendrimers for the functional and adaptive delivery of siRNA therapeutics.
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机译：小干扰RNA（siRNA）被基于RNA干扰，作为治疗范围广泛的疾病的有希望的治疗策略。然而，安全有效地将siRNA治疗剂进入靶细胞内部仍然具有挑战性。在此，我们公开了由疏水性的两种脂质样烷基链和亲水性聚（赖氨酸）树枝与不同几代（2C 18-κ2和2C 18 -KK 2 K 4）组成的新型两亲肽树枝状大分子（AMPD），作为siRNA的纳米粒子送货。这些AMPD能够自组装成能够将siRNA分子诱发到纳米颗粒中以保护siRNA免受酶促降解并促进有效的细胞内摄取而没有明显毒性的纳米颗粒。有趣的是，凭借疏水性脂质状实体和亲水性聚（赖氨酸）的最佳平衡，AMPD 2C 18 -KK 2 K 4轴承较大的亲水性树突可以封装siRNA形成稳定，但更准备好拆卸复合物，从而弥合与AMPD 2C 18 -KK 2轴承较小的树突相比，导致更有效的siRNA释放和更好的基因沉默效果。额外的研究证实，2C 18 -KK 2 K 4可以利用脂质和肽树枝状型载体的优点，用于有效的siRNA递送。统称，我们的AMPD的纳米载波确实代表了一个安全有效的siRNA递送系统。我们的研究结果还提供了一种新的术语，用于调节自组装两亲肽树枝状大分子，用于siRNA治疗剂的功能和适应性递送。
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