Nanoparticles are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of nanoparticle clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of nanoparticles in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic nanoparticles without any "background" from blood or tissues, which is a significant advantage over other techniques, e.g., optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the nanoparticle clearance from the flow in the user-defined mediums, e.g., those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of nanoparticles. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of nanoparticle sequestration and for development of novel "stealth" nanoagents.