K16ApoE is a brain-targeted drug carrier that can deliver drugs throughout the brain and maintain sustained activity during delivery. However, related studies have revealed that K16ApoE has acute and high toxicity, and its toxicological mechanism remains unknown. Our previous experiments found that K16ApoE affects the blood state of mice. Thus, we performed a hemolysis assay to investigate whether K16ApoE could induce hemolysis, but we found that K16ApoE was unable to lyse red blood cells at lethal doses. Then, we monitored cerebral blood flow and perfusion after the mice received incremental doses of K16ApoE and found that K16ApoE could suddenly interrupt the blood flow and reduce the perfusion in the brain. K16ApoE could also disrupt the consistency of cerebral perfusion. Last, we examined the blood cells under the microscope and found that K16ApoE caused the cells to clump in the plasma and increase blood viscosity. Based on these findings, we confirmed that the toxicity of K16ApoE is mainly in the blood. The mechanism is that K16ApoE induces blood cell aggregation and interrupts blood flow.