Macropinocytosis is an evolutionarily conserved form of endocytosis in which cells non-selectively engulf extracellular fluid and solutes, forming large vesicles (0.2–5 μm) known as macropinosomes. This process occurs across a wide range of organisms and serves diverse physiological and pathological functions [1,2]. In the social amoeba Dictyostelium discoideum, macropinocytosis is the primary mechanism of nutrient uptake under axenic culture conditions. In mammals, it facilitates antigen sampling, membrane repair, and synaptic regulation [3, 4, 5]. In addition, pathogens hijack the mechanism to invade host cells, and cancer cells exploit it to scavenge extracellular nutrients.

Macropinocytosis is initiated by actin-driven membrane remodeling, leading to the formation of linear or circular ruffles, referred to as macropinocytic cups. These structures develop from signaling microdomains enriched in specific phosphoinositides and small GTPases, which promote actin polymerization and membrane protrusion. Cup closure generates macropinosomes, which quickly enter a maturation phase, reducing their surface area and volume to concentrate the contents and recycle membrane components. The vesicles further traffic through the endolysosomal system, fusing with endosomes and lysosomes for cargo degradation, whereas non-degradable material is exocytosed in certain cell types (Figure 1a).

This review aims to provide a brief overview of recent advances in macropinocytosis research, highlighting key discoveries and developments in the field.