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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 nanove-hicles 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 genera-tions,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.