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The surface charge of a nanostructure plays a critical role in modulating blood circulation time, nanostructure–cell interaction, and intracellular events. It is unfavorable to have positive charges on the nanostructure surface before arriving at the disease site because positively charged nanostructures interact strongly with blood components, resulting in rapid clearance from the blood, and suboptimal targeted accumulation at the tumor site. Once at the tumor site, however, the positive charge on the nanostructure surface accelerates uptake by tumor cells and promotes the release of payloads from the lysosomes to the cytosol or nucleus inside cells. Thus, the ideal nanocarrier systems for drug delivery would maintain a neutral or negatively charged surface during blood circulation but would then generate a positive surface charge after accumulation at the tumor site or inside the cancer cells. This Progress Report focuses on the design and application of various neutral or negatively charged nanostructures that can generate a positive charge in response to the tumor microenvironment or an external stimulus.