Manipulation of the ubiquitin-proteasome pathway to achieve targeted silencing of cellular proteins has emerged as a reliable and customizable strategy for remodeling the mammalian proteome. One such approach involves engineering bifunctional proteins called ubiquibodies that are comprised of a synthetic binding protein fused to an E3 ubiquitin ligase, thus enabling post-translational ubiquitination and degradation of a target protein. Here, we have designed a panel of new ubiquibodies based on E3 ubiquitin ligase mimics from bacterial pathogens that are capable of effectively interfacing with the mammalian proteasomal degradation machinery for selective removal of proteins of interest. One of these, the Shigella flexneri effector protein IpaH9.8 fused to a fibronectin type III (FN3) monobody that specifically recognizes green fluorescent protein (GFP), was observed to potently eliminate GFP and its spectral derivatives as well as 15 different FP-tagged mammalian proteins that varied in size (27–179 kDa) and subcellular localization (cytoplasm, nucleus, membrane-associated, and transmembrane). We further demonstrated the modularity and flexibility of IpaH9.8 by redirecting its activity towards the disease relevant proteins SHP2, KRas, and ERK2 through the use of binding domains identified in literature as well as novel binding domains we isolated using yeast surface display. To demonstrate therapeutically relevant delivery of ubiquibodies, we investigated two approaches: endowment of ubiquibodies with a cell-penetrating peptide domain and packaging of mRNA encoding the GFP-specific ubiquibody in bioinspired nano-sized complexes. The resulting nanoplexes delivered ubiquibody mRNA in a manner that caused efficient target depletion in cultured mammalian cells stably expressing GFP as well as in transgenic mice expressing GFP ubiquitously. Lastly, we discuss preliminary designs for controlling ubiquibody behavior with spatial and temporal control. Overall, our results suggest that IpaH9.8-based ubiquibodies are a highly modular proteome editing technology with the potential for pharmacologically modulating disease-causing proteins.