Developing vehicles for the delivery of therapeutic molecules, like siRNA, is an area of active research. Nanoparticles composed of bovine serum albumin, stabilized via the adsorption of poly-L-lysine (PLL), have been shown to be potentially inert drug-delivery vehicles. With the primary goal of reducing nonspecific protein adsorption, the effect of using comb-type structures of poly(ethylene glycol) (1？kDa, PEG) units conjugated to PLL (4.2 and 24？kDa) on BSA-NP properties, apparent siRNA release rate, cell viability, and cell uptake were evaluated. PEGylated PLL coatings resulted in NPs with -potentials close to neutral. Incubation with platelet-poor plasma showed the composition of the adsorbed proteome was similar for all systems. siRNA was effectively encapsulated and released in a sustained manner from all NPs. With 4.2？kDa PLL, cellular uptake was not affected by the presence of PEG, but PEG coating inhibited uptake with 24？kDa PLL NPs. Moreover, 24？kDa PLL systems were cytotoxic and this cytotoxicity was diminished upon PEG incorporation. The overall results identified a BSA-NP coating structure that provided effective siRNA encapsulation while reducing -potential, protein adsorption, and cytotoxicity, necessary attributes for in vivo application of drug-delivery vehicles. 1. Introduction Short interfering RNA (siRNA) is extremely promising for the therapeutic treatment of a myriad of diseases; however, its clinical application has hitherto been hindered by an apparent inability to control its delivery. The use of NP based drug delivery vehicles presents several advantages over conventional delivery stratagems, including the fact that they may be used for precise tissue targeting, remain in blood for a prolonged time, and be immediately injected into the systemic circulation. Furthermore, favorable tissue responses have been observed for decreasing particle sizes [1] and a multitude of covalent and noncovalent modifications of NP surfaces can be achieved, aspects that facilitate the design of more effective carriers. In particular, BSA-based NPs have many advantageous qualities [2]: presence of a hydrophobic core facilitating delivery of hydrophobic drugs, a natural abundance in plasma, relative stability and inertness in biochemical pathways, availability, and a relatively benign in vivo biological fate [3]. Unlike NPs fabricated from synthetic polymers, it is thought that the natural protein removal mechanisms will result in a reduced overall toxicity related to the application of BSA NPs [3]. That said, an important step in facilitating the
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