The potential of RNA interference (RNAi)-based therapeutics for cancer has received much attention; however, delivery of RNAi effectors, such as small interfering RNA (siRNA), remains an obstacle to clinical translation. Non-viral delivery vectors have been used extensively to enhance siRNA delivery. Recently, the potential of gold nanoparticles (AuNPs) for transporting drugs, proteins and genetic materials has been demonstrated. Previously, our laboratory synthesised positively charged, surfactant-free AuNPs in water by the reduction of gold (III) chloride (AuCl3) using hydroxylamine hydrochloride (NH2OH center dot HCl) in the presence of L-cysteine methyl ester hydrochloride (HSCH2CH(NH2)COOCH3 center dot HCl) as a capping agent. These AuNPs, which achieve higher cell viability in comparison to cetyl trimethyl ammonium bromide (CTAB, a surfactant)-capped counterparts, have demonstrated potential for siRNA delivery. However, it is well known that systemic administration of cationic delivery systems without biological stablising moieties causes non-specific binding with negatively charged serum proteins, resulting in particle aggregation and opsonisation. Consequently, highly stable AuNPs capped with L-cysteine methyl ester hydrochloride conjugated to poly(ethylene glycol) (PEG) were synthesised in this study. PEGylation enhanced the biocompatibility of the AuNPs by reducing toxicity in a range of cell types, by inhibiting interaction with serum proteins thus avoiding aggregation, and, by providing protection against degradation by nucleases. Moreover, these PEGylated AuNPs formed nanoparticles (NPs) with siRNA (which was first compacted with protamine), and had a diameter within the nanoscale range (similar to 250 nm) and a near neutral surface charge (similar to 10 mV). In the future a bifunctional PEG chain on the AuNPs (i.e., SH-PEG-NH2, SH-PEG-COOH) will be used to facilitate conjugation of a targeting ligand to enhance cell specific uptake. (C) 2015 Elsevier B.V. All rights reserved.