The clearance of nanoparticles from the body is a critical aspect of their biomedical applications, particularly in drug delivery and diagnostic imaging. Renal and hepatic pathways serve as the primary routes for nanoparticle elimination, while the reticuloendothelial system (RES) plays a significant role in sequestering nanoparticles, leading to accumulation in organs such as the liver, spleen, and lymph nodes. Understanding these processes is essential for designing nanoparticles with optimal circulation times and minimal off-target effects.

Renal clearance is highly dependent on nanoparticle size, surface charge, and composition. The glomerular filtration barrier in the kidneys permits the passage of molecules smaller than approximately 5.5 nm in hydrodynamic diameter. Nanoparticles below this threshold are efficiently filtered and excreted in urine, while larger particles are retained in circulation. Studies have shown that gold nanoparticles with diameters below 6 nm exhibit rapid renal clearance, whereas those exceeding 8 nm are predominantly retained. Surface modifications, such as polyethylene glycol (PEG) coating, can further influence renal excretion by altering hydrodynamic size and reducing protein adsorption. However, even small nanoparticles may experience delayed clearance if they aggregate in biological fluids or interact with serum proteins.

Hepatic clearance involves the uptake of nanoparticles by liver sinusoidal endothelial cells and Kupffer cells, followed by biliary excretion. Nanoparticles larger than the renal filtration threshold are often directed to the liver, where their fate is determined by size, surface chemistry, and shape. Particles between 10 and 200 nm are readily internalized by hepatocytes or Kupffer cells, depending on surface properties. Neutral or slightly negative charges tend to minimize nonspecific uptake, while positively charged nanoparticles are more likely to be sequestered due to electrostatic interactions with cell membranes. Biliary excretion typically requires nanoparticles to undergo further processing into smaller metabolites, as the bile canaliculi have a size exclusion limit of approximately 5 nm. Consequently, larger nanoparticles may remain trapped in hepatocytes or Kupffer cells for extended periods.

The reticuloendothelial system, comprising macrophages in the liver, spleen, and bone marrow, plays a dominant role in nanoparticle clearance. Kupffer cells in the liver and red pulp macrophages in the spleen actively phagocytose nanoparticles, particularly those with hydrophobic or opsonized surfaces. This sequestration leads to significant accumulation in these organs, which can be both advantageous and problematic. For instance, nanoparticles designed for liver-targeted therapies benefit from RES uptake, while systemic delivery applications require strategies to evade macrophage recognition. PEGylation is a common approach to reduce opsonization and prolong circulation, but even PEG-coated nanoparticles are eventually cleared by the RES over time.

Macrophage sequestration dynamics are influenced by nanoparticle physicochemical properties. Spherical particles are internalized more efficiently than rod-shaped or filamentous structures due to differences in membrane wrapping efficiency. Surface roughness and elasticity also play roles, with softer nanoparticles exhibiting reduced phagocytic uptake compared to rigid ones. The protein corona that forms on nanoparticles in biological fluids further modulates interactions with macrophages. Opsonins such as immunoglobulins and complement proteins enhance phagocytosis, while dysopsonins like albumin can suppress it. The balance between these factors determines the rate and extent of nanoparticle accumulation in RES organs.

Size-dependent filtration thresholds are critical for predicting nanoparticle biodistribution. Below 5.5 nm, renal clearance dominates. Between 5.5 and 10 nm, nanoparticles may undergo both renal and hepatic clearance, depending on surface properties. Above 10 nm, hepatic and RES pathways prevail, with minimal renal excretion. Nanoparticles exceeding 200 nm are primarily trapped in the spleen due to mechanical filtration in the interendothelial slits of the red pulp. These thresholds are not absolute, as surface modifications can shift the balance between clearance mechanisms.

Long-term accumulation in RES organs raises concerns about potential toxicity. Persistent nanoparticle retention in the liver and spleen may induce inflammatory responses or oxidative stress, particularly with metallic or metal oxide nanoparticles. Biodegradable materials such as polymeric or lipid-based nanoparticles are often preferred to mitigate these risks, as they can be broken down into nontoxic byproducts over time. However, even biodegradable nanoparticles may exhibit prolonged residence in macrophages if their degradation kinetics are slow.

Efforts to engineer nanoparticles for controlled clearance include size tuning, surface functionalization, and biomimetic coatings. For example, zwitterionic coatings have been shown to reduce protein adsorption and RES uptake more effectively than PEG in some cases. Alternatively, transient modulation of macrophage activity using pharmacological agents has been explored to delay nanoparticle sequestration. Despite these advances, achieving precise control over clearance pathways remains a challenge due to the complexity of biological systems.

In summary, renal and hepatic clearance pathways, along with RES sequestration, govern the fate of nanoparticles in vivo. Size, surface chemistry, and shape dictate whether nanoparticles are excreted rapidly or accumulate in specific organs. Understanding these mechanisms is crucial for optimizing nanoparticle design for therapeutic and diagnostic applications while minimizing unintended biodistribution and toxicity. Future research should focus on refining strategies to modulate clearance behavior, particularly for nanoparticles intended for systemic delivery or repeated administration.