Macropinocytosis as a cell entry route for peptide-functionalized and bystander nanoparticles

Endocytic pathways provide the primary route for therapeutic and diagnostic nanoparticles (NPs) to enter cells and subcellular compartments. A better understanding of these cell entry processes will not only aid in nanomaterial applications but also broaden our knowledge of cell biology. Among the endocytic routes, macropinocytosis has unique characteristics for engulfing NPs and other large cargo, yet its molecular machinery and involvement in NP uptake are far less characterized relative to other pathways. In this review, we summarize the current knowledge on the macropinocytic machinery, and its involvement in NP internalization. Particularly, we differentiate ligand (specifically peptide)-functionalized and unfunctionalized NPs (bystander NPs). While most of previous research focused on ligand-functionalized NPs, we showcase here a synergistic effect between these two NP types during their cell entry through receptor-mediated macropinocytosis. The regulation of NP uptake efficiency by extracellular amino acids is also highlighted in the context of interconnections between macropinocytosis and metabolic signaling. These discussions may fuel future research interests in improving NP internalization through this pathway, and open a new avenue to study the interplay among endocytosis, metabolism and nanomedicine.

Automated summary

The endocytic pathways are crucial for the uptake of nanoparticles into cells and subcellular compartments. Macropinocytosis stands out for its unique ability to engulf large cargo, though its molecular mechanisms and role in nanoparticle uptake are not well understood. This review focuses on the macropinocytic machinery and its involvement in nanoparticle internalization, highlighting the synergistic effect between ligand-functionalized and unfunctionalized nanoparticles. The regulation of nanoparticle uptake efficiency by extracellular amino acids and the interconnectedness of macropinocytosis, metabolism, and nanomedicine are also discussed to inspire future research.