Receptor-mediated transcytosis (RMT)

Receptor-mediated transcytosis (RMT) is a specialized physiological process that facilitates the active transport of macromolecules across polarized cellular barriers, such as the blood-brain barrier (BBB) and intestinal epithelium [1, 3]. The mechanism initiates when a ligand or therapeutic vehicle binds to specific cell-surface receptors on the luminal or apical membrane, triggering clathrin- or caveolin-mediated endocytosis into intracellular vesicles [4, 13]. Unlike typical endocytic pathways that lead to lysosomal degradation, RMT-bound vesicles are sorted to bypass the lysosome and are trafficked across the cytoplasm to the opposite abluminal or basolateral membrane for exocytic release [10]. In the context of drug delivery, RMT is a critical strategy for the non-invasive delivery of large-molecule therapeutics—including antibodies, enzymes, and nanoparticles—to the central nervous system (CNS) [6, 11]. It effectively uses endogenous receptors like the transferrin receptor (TfR) or insulin receptor (IR) as "molecular Trojan horses" to shuttle payloads into the brain parenchyma [5, 8]. This pathway is instrumental in treating neurodegenerative diseases and lysosomal storage disorders, as seen with clinically approved therapies like pabinafusp alfa [5, 7]. However, therapeutic success depends on optimizing ligand-receptor affinity to ensure effective release at the target site while avoiding entrapment within the endothelial cells [12].

Other names

RMTVesicular transcytosisTranscellular transportMolecular Trojan horse pathway

Binding to a luminal cell-surface receptor followed by vesicular internalization, endosomal sorting to avoid degradation, and exocytosis at the abluminal membrane [4, 10].