Nanoparticle Cellular Uptake Mechanisms in Drug Delivery

Nanoparticles have emerged as versatile carriers for targeted drug delivery owing to their tunable physicochemical properties and capacity to traverse biological barriers. Cellular entry of nanoparticles is predominantly mediated by endocytic pathways, which can be broadly classified into clathrin-mediated endocytosis, caveolin-mediated endocytosis, macropinocytosis and phagocytosis. The choice of pathway depends on particle size, shape, surface charge and ligand decoration. Following internalisation, nanoparticles traffic through early endosomes, late endosomes and lysosomes or escape into the cytosol, thus dictating intracellular fate and therapeutic efficacy. Exocytosis and recycling processes further regulate nanoparticle retention and clearance. Understanding these mechanisms has guided the rational design of smart nanosystems with enhanced targeting, controlled release and minimal off-target toxicity. Advances in high-resolution imaging and quantitative assays have begun to reveal rapid uptake kinetics, vesicular maturation dynamics and the interplay between nanoparticle clustering and intracellular transport. Such insights are crucial for translating nanoparticle-based therapies into clinical practice, particularly in oncology, gene therapy and precision medicine.

Research from Nature Portfolio

Seminal work has employed correlative fluorescence and plasmonic imaging to map nanoparticle clustering and transport within living cells. It revealed that gold nanoparticles enter via multiple endocytic routes and remain mostly as single entities during initial membrane invagination. Clustering emerges during vesicular maturation, with larger aggregates exhibiting slower intracellular transport. This study underscored the importance of controlling nanoparticle aggregation state and surface chemistry to optimise cytosolic delivery and avoid lysosomal degradation. The findings have informed the engineering of theranostic carriers that balance stability in circulation with efficient endosomal escape.

Nanoparticle Cellular Uptake Mechanisms in Drug Delivery publication trend

The graph below shows the total number of articles in nanoparticle cellular uptake mechanisms in drug delivery across all publications each year (not limited to Nature Index journals).

Technical terms

Endocytosis: Active cellular process by which extracellular substances are internalised via vesicle budding from the plasma membrane.

Clathrin-mediated endocytosis: Selective uptake pathway involving clathrin protein coats that form vesicles around specific cargo.

Caveolin-mediated endocytosis: Lipid raft-associated pathway employing caveolin proteins to internalise small vesicles rich in cholesterol and sphingolipids.

Macropinocytosis: Non-selective engulfment of extracellular fluid and particles into large vesicles known as macropinosomes.

Exocytosis: Process of vesicular fusion with the plasma membrane to release internalised materials or recycling vesicle membranes back to the cell surface.

References

1. Rapid Internalization of Nanoparticles by Human Cells at the Single Particle Level. ACS Nano (2023).
2. Bridging Smart Nanosystems with Clinically Relevant Models and Advanced Imaging for Precision Drug Delivery. Advanced Science (2024).
3. Cellular journey of nanomaterials: Theories, trafficking, and kinetics. Aggregate (2023).
4. Real-time visualization of clustering and intracellular transport of gold nanoparticles by correlative imaging. Nature Communications (2017).