RNA interference (RNAi) is a powerful tool to target and knockdown gene expression in a sequencespecific manner. RNAi can be achieved by the intracellular introduction of SiRNA; however, intracellular SiRNA delivery remains a challenging obstacle. Herein we describe the use of bioreducible nanoparticles formed using poly(beta-amino ester)s (PBAEs) for safe and efficient SiRNA delivery. Methods for polymer synthesis, nanoparticle formation, and SiRNA delivery using these particles are described. A template protocol for nanoparticle screening is presented and can be used to quickly optimize SiRNA delivery for novel applications.