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Self-assembled cationic block copolymer nanoparticles have been extensively studied as a vehicle for intracellular drug delivery, with multiple design rules outlined for optimal cargo loading and delivery. In contrast, an alternative polymer architecture, graft copolymer, has not been comprehensively explored. This study aims to explore the self-assembly phase space, as well as the bioactivity of this polymer. Here we synthesize libraries of chose poly(ethylene glycol) methacrylate-co-(2-diethylamino) methacrylate-co-butyl methacrylate (PEGMA-co-EB), varying the hydrophobic molecular weight, hydrophilic weight fraction and graft lengths. We study the effects of each parameter on their nanoparticle self-assembly behavior and bioactivity. We discovered that the different polymer architecture caused different behavior from block copolymer analogues: spherical bilayer self-assembly at high hydrophobic molecular weight domains and decreasing endosomolytic activity with increasing graft density. In addition, we demonstrated successful and effective drug delivery performance of a hydrophilic drug in vitro with these polymers in a spherical bilayer format. Our findings highlighted an opportunity to use these polymers as versatile and highly endosomolytic drug delivery vehicles. With our study, we call for additional exploration of the use of cationic graft copolymers as a novel solution for intracellular drug delivery.