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The cellular and endosomal membranes represent a significant delivery barrier in cytosolically active therapeutics. To address this challenge, several investigators have developed cationic and pH-responsive self-assembling polymeric nanoparticles as a drug delivery vehicle to enhance cellular uptake and endosomal escape of drug cargoes into the cytosol. To date, these approaches have largely leveraged homopolymers or block copolymer architectures – as such, design rules for other polymer architectures remain poorly characterized. For this project, we fill that gap with exploration of a PEG-grafted copolymer system. Libraries of poly[poly(ethylene glycol) methyl ether methacrylate-co-butyl methacrylate-co-(2-diethylamino) ethyl methacrylate] (PEGMA-co-EB) graft copolymers with varying hydrophobic molecular weight, hydrophilic volume fraction and graft lengths was synthesized and characterized. They were then screened for hydrodynamic sizes, endosomolytic activity and drug delivery competency in vitro. Promising formulations were applied in a murine B16.F10 melanoma utilizing 2’4’-cGAMP, a STING agonist, as the therapeutic agent and cargo. From our in vitro experiments, we discovered that formulations with low hydrophilic volume fraction (W_PEG ~ 20%), moderate hydrophobic molecular weight (MW ~ 30 kDa), and short graft lengths (MW_PEG ~ 300 Da) self-assembles into larger-sized particles and exhibit superior bioactivity. These formulations, when applied to our in vivo tumor model, were able to better slow tumor growth compared to our free drug control. Collectively, our results highlighted design rules for application of a cationic graft copolymer structure for drug delivery, and adding understanding of another tool in the drug delivery arsenal.