Amphiphilic peptide dendrimer-based nanovehicles for safe and effective siRNA delivery

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.

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

“…, virus protein facilitated membrane fusion and electric field mediated electroporation), to facilitate early endosomal escape of siRNA and thereby increase the efficacy of siRNA-mediated gene silencing. Consequently, various delivery carriers, such as lipid nanoparticles, − polymers, ,− inorganic nanoparticles, − peptides, − extracellular vesicles, ,− and siRNA-conjugates − have been developed to transport siRNA effectively and specifically to the intended site in a gretaer amount.…”

A Self-Assembling Amphiphilic Peptide Dendrimer-Based Drug Delivery System for Cancer Therapy

“…AmPDs composed of hydrophobic C 18 alkyl chain and different hydrophilic poly(L-lysine) peptide dendrons (AmPD KK 2 and AmPD KK 2 K 4 ) were synthesized according to the strategy described in Schemes S1–S4 (Supplementary Materials ). Different generations of Boc groups protected hydrophilic poly(L-lysine) dendrons bearing alkyne groups, and the hydrophobic C 18 alkyl chains bearing an azide group were prepared using a previously reported protocol [ 17 , 24 , 25 ]. Then, hydrophilic dendrons were covalently conjugated with the hydrophobic alkyl chains via robust and efficient Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) ‘click’ reaction to yield AmPDs with protecting groups.…”

“…The synthetic protocol of hydrophobic alkyl chain and peptide dendrons was optimized (Supplementary Material) according to the reported literature [ 17 , 24 , 25 ]. AmPD 2–3, C 18 -N 3 , CuSO 4 ·5H 2 O and NaAsc ( l -Ascorbic Acid Sodium Salt) were dissolved in anhydrous THF under nitrogen atmosphere.…”

“…Recently, to combine the excellent properties of peptide dendrimers (such as their protein-like properties, good biocompatibility, etc. [ 21 , 22 ]), we developed amphiphilic peptide dendrimers (AmPDs), which carry peptide dendrons as hydrophilic heads for the delivery of nucleic acid therapeutics [ 23 , 24 ].…”

Review: Development of SARS-CoV-2 immuno-enhanced COVID-19 vaccines with nano-platform

“…The advantages of dendrimers are the ability to modify the cavities to incorporate hydrophilic or hydrophobic molecules, modify the end-groups to attach peptide for targeting purposes, and they were approved for clinical applications [184]. Polyamidoamine (PAMAM) dendrimers are promising as nanocarriers of vaccines because their positive charges can form complex via electrostatic interaction with negatively charged of plasmid DNA molecules [185,186]. Recently, a novel amphiphilic peptide dendrimer (AmPDs) was developed for safe and effective RNA delivery.…”