Silencing disease-related genes in the central nervous system (CNS) using short interfering RNA (siRNA) holds great promise for treating neurological disorders. Yet, delivery of RNAi therapeutics to the brain poses major challenges to non-viral systems, especially when considering systemic administration. Cationic nanoparticles have been widely investigated for siRNA delivery, but the tendency of these to aggregate in physiological environments limits their intravenous application. Thus, strategies to increase the stability of nanoparticles have been developed. Here, we investigated the ability of modified cationic amphiphilic or PEGylated amphiphilic cyclodextrins (CD) to formulate stable CD.siRNA nanoparticles. To this end, we describe a simple method for post-modification of pre-formed cationic CD.siRNA nanoparticles at their surface using PEGylated CDs of different PEG lengths. PEGylatedCD.siRNA nanoparticles presented reduced surface charges and increased stability in physiological salt conditions. Stability of PEGylated CD.siRNA nanoparticles in vitro increased with both PEG length and PEG density at the surface. Furthermore, in a comparative pharmacokinetic study, increased systemic exposure and reduced clearance were achieved with CD-formulations when compared to naked siRNAs. However, no significant differences were observed among non-PEGylated and PEGylated CD.siRNAs suggesting that longer PEG lengths might be required for improving stability in vivo.