Therapeutic proteins have attracted significant attention as they perform vital roles in various biological processes. The delivery of therapeutic proteins to target sites is, however, challenging due to their intrinsic sensitivity to different environmental conditions. Polymeric nanoparticles (NPs) can offer not only physical protection from environmental stimuli but also targeted delivery of such proteins to specific sites. In particular, NPs containing charged polymers are preferred for many applications as they provide gentle protection through electrostatic interactions. Moreover, most organs exhibit a specific pH, and by tuning the extent of the electrostatic interactions and contact duration between the target organ and polymeric NPs, the intracellular uptake of the latter and thus long-term therapeutic efficacy can be optimized. In this article, we will critically discuss the design considerations of charged polymeric NPs, strategies for and routes of protein delivery and how these are influenced depending on the choice of delivery route.