Abstract
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 (2C18-KK2 and 2C18-KK2K4) 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 2C18-KK2K4 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 2C18-KK2 bearing smaller dendron. Additional studies confirmed that 2C18-KK2K4 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.
Highlights
Small interfering RNA, a double-stranded RNA molecule with 19–23 nucleotides, has the powerful capacity to silence the expression of any gene, such as disease-linked genes, with complementary mRNAChi Ma and Dandan Zhu have contributed to this work.sequence via Watson–Crick base pairing (Bajan and Hutvagner 2020; Castanotto and Rossi 2009; Weng et al 2019)
amphiphilic peptide dendrimers (AmPDs) 2C18-KK2 was coupled with the protected lysine (Boc-Lys-Boc-OH) and followed the deprotection of Boc to obtain AmPD 2C18-KK2K4
The measurements by dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that the assemblies formed by AmPDs were spherical and *200 nm in diameter (Fig. 2B and C)
Summary
Small interfering RNA (siRNA), a double-stranded RNA molecule with 19–23 nucleotides, has the powerful capacity to silence the expression of any gene, such as disease-linked genes, with complementary mRNAChi Ma and Dandan Zhu have contributed to this work.sequence via Watson–Crick base pairing (Bajan and Hutvagner 2020; Castanotto and Rossi 2009; Weng et al 2019). SiRNA-based RNA interference (RNAi) (Castanotto and Rossi 2009; Kay 2015; Setten et al 2019; Wittrup and Lieberman 2015) is exploited as a promising therapeutic modality for the treatment of both genetic and acquired diseases, culminating with the approval of siRNA therapeutics PatisiranÒ and GivosiranÒ (Ledford 2018; Mullard 2020) by the USA Food and Drug Administration (FDA) and European Commission (EC). The development of siRNA-based drugs relies on the exploitation of safe and effective delivery vehicles to deliver siRNA molecules to the cytoplasm of the target cell. Cationic lipids and polymer are the two most advanced representatives (Li et al 2018; Ozpolat et al 2014; Wagner 2012; Wu et al 2017) They are able to form stable complexes with siRNA via electrostatic interactions, protect it from enzymatic degradation, and promote cellular uptake of siRNA. Amphiphilic dendrimers married the characteristics of dendrimers and the self-assembling feature of lipids, taking the advantages of both dendrimers and lipids carriers for excellent performance on the transportation of siRNA therapeutics (Chen et al 2016; Dong et al 2018; Liu et al 2014, 2015, 2016; Percec et al 2010; Yu et al 2012)
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