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Transcytosis

Transcytosis is a cellular process involving the vesicular transport of macromolecules, such as proteins and lipids, from one side of a polarized cell to the other, enabling the selective movement of substances across physiological barriers while preserving the distinct compositions of adjacent compartments.^[1] The concept was first proposed by George Palade in the 1950s to explain capillary permeability.^[1] This mechanism combines endocytosis at one plasma membrane domain, intracellular trafficking through vesicles, and exocytosis at the opposing domain, often mediated by specific pathways like clathrin-coated pits or caveolae.^[2] In endothelial and epithelial cells, transcytosis plays a critical role in maintaining homeostasis by facilitating the transport of essential molecules, including nutrients like iron via transferrin receptor-mediated endocytosis and immunoglobulins such as polymeric IgA through the polymeric immunoglobulin receptor.^[1] For instance, at the blood-brain barrier, receptor-mediated transcytosis allows limited passage of insulin and low-density lipoprotein while restricting larger or non-specific cargos to protect the central nervous system.^[3] Adsorptive transcytosis, driven by electrostatic interactions, further enables the uptake of cationic substances, though it is less selective and can contribute to pathological leakage in conditions like stroke.^[3] The process is regulated by molecular components including SNARE proteins for vesicle fusion, Rab GTPases for trafficking, and lipids like phosphatidylinositol 3-phosphate, ensuring directional transport in polarized cells.^[1] Dysregulation of transcytosis contributes to various diseases, such as Alzheimer's, and serves as a target for drug delivery strategies across barriers.^[4]^[3] Overall, transcytosis exemplifies an evolutionarily conserved strategy for transcellular exchange in multicellular organisms, balancing permeability and protection across key tissue interfaces.^[1]

Introduction

Definition

Transcytosis is a specialized form of transcellular transport that enables the movement of macromolecules across polarized cells, such as epithelial and endothelial cells, through a process involving endocytosis at one plasma membrane, vesicular trafficking across the cytoplasm, and exocytosis at the opposite membrane.^[2]^[5] This mechanism allows relatively large substances, typically exceeding 10 kDa, to be shuttled vectorially from one extracellular compartment to another without mixing with the cell's endolysosomal degradation pathways.^[6] Unlike paracellular transport, which occurs between adjacent cells through tight junctions, or simple diffusion across the lipid bilayer limited to small, non-polar molecules, transcytosis provides a regulated, energy-dependent route for selective macromolecular passage in a directional manner.^[7]^[6] This polarized nature is particularly prominent in barrier-forming tissues, where it maintains tissue homeostasis by directing cargo from apical to basolateral surfaces or vice versa.^[5] Representative examples of transcytosed molecules include polymeric immunoglobulin A (IgA), which is transported across mucosal epithelia to provide immune protection at secretory surfaces; iron bound to transferrin, facilitating nutrient delivery across endothelial barriers; and low-density lipoprotein (LDL), which crosses vascular endothelium to support cholesterol distribution in tissues.^[8]^[9]^[10] These processes highlight transcytosis's role in immune defense, nutrient uptake, and lipid metabolism, often involving specific vesicular pathways for efficient trafficking.^[11]

Historical Development

Early observations of vesicular transport across epithelial barriers emerged in the mid-20th century, particularly through electron microscopy studies of nutrient absorption in the intestinal epithelium. In 1959, Samuel L. Palay and Leonard J. Karlin provided seminal evidence for the pathway of fat absorption, demonstrating that dietary lipids were internalized via pinocytotic vesicles at the apical surface of enterocytes, transported across the cell in membrane-bound compartments, and released at the basolateral side into lacteals.^[12] This work highlighted the role of vesicular mechanisms in macromolecular transport, initially termed "cytopempsis" or pinocytosis, and laid foundational insights into transcellular movement beyond simple diffusion. The concept of transcytosis as a directed, vectorial process was formalized in the late 1970s through studies on capillary endothelium. Drawing from George E. Palade's earlier electron microscopy observations of vesicular shuttling in endothelial cells during the 1950s and 1960s, Nicolae Simionescu coined the term "transcytosis" in 1979 to describe the specific apical-to-basolateral or vice versa transport of plasma macromolecules, such as albumin and low-density lipoprotein (LDL), via plasmalemmal vesicles in the arterial endothelium.^[13] This terminology distinguished transcytosis from non-directional endocytosis, emphasizing its role in maintaining vascular permeability and nutrient delivery. Key milestones in the 1980s included the elucidation of receptor-mediated transcytosis for immunoglobulins. Keith E. Mostov and Günter Blobel identified the polymeric immunoglobulin receptor (pIgR) as the mediator of dimeric IgA transport across epithelial barriers, such as in the liver and intestine, where it binds IgA at the basolateral surface, traffics it vectorially, and releases it apically as secretory IgA.^[14] This discovery, confirmed through cell culture models like MDCK cells, established transcytosis as a critical mechanism for mucosal immunity.^[15] Advances in the 2000s leveraged genetic tools to dissect vesicular pathways, particularly the involvement of caveolae. In 2001, Schubert et al. demonstrated using caveolin-1 knockout mice that ablation of this protein, essential for caveolae formation, significantly reduced albumin transcytosis across endothelial barriers, confirming caveolae as a primary route for fluid-phase and receptor-mediated transport.^[16] These findings shifted understanding toward caveolae-dependent mechanisms in endothelial permeability. In the 2020s, research has further solidified the pathological relevance of transcytosis, with 2025 studies confirming caveolae-mediated LDL transport in atherosclerosis models. For instance, investigations using advanced imaging and genetic perturbations in mouse aortas revealed that caveolin-1 drives LDL transcytosis into the intima, promoting plaque formation, and identified myosin-9 as a regulator enhancing this process under hyperlipidemic conditions.^[17] These developments underscore transcytosis as a therapeutic target for cardiovascular disease.

Mechanisms

Vesicular Transport Process

Transcytosis involves the directed vesicular transport of macromolecules across polarized cells, such as epithelial and endothelial cells, from one plasma membrane domain to the opposite one, preserving cellular polarity through sequential endocytic, sorting, and exocytic events.^[1] This process enables selective passage of cargo like antibodies, nutrients, and proteins while maintaining barrier integrity, with vesicles typically measuring 50-100 nm in diameter to facilitate efficient intracellular movement.^[18] The process begins with endocytosis at either the apical or basolateral membrane, depending on the direction of transport. In clathrin-dependent endocytosis, cargo binds receptors and is internalized via clathrin-coated pits forming early endosomes, as seen in the transport of polymeric immunoglobulin A (pIgA) across epithelial cells.^[1] Alternatively, caveolae-mediated endocytosis predominates in endothelial cells, where flask-shaped invaginations enriched in caveolin-1 internalize molecules like albumin through cholesterol-dependent mechanisms, rapidly forming vesicles within seconds.^[18] These initial endocytic vesicles, often 50-70 nm in size for caveolae, capture extracellular material without immediate degradation.^[1] Following endocytosis, intracellular sorting and trafficking direct the vesicles across the cytoplasm while avoiding lysosomal fusion. Cargo is routed through recycling endosomes—such as early endosomes marked by Rab5 and EEA1, progressing to common or apical recycling endosomes with Rab11 and Rab25—to prevent degradation, as exemplified by pIgA transcytosis in polarized MDCK cells.^[18] This sorting is coupled with long-range trafficking along microtubules, powered by motor proteins like dynein (for minus-end directed apical movement) and kinesin (for plus-end directed basolateral transport), ensuring bidirectional polarity in cells like enterocytes.^[1] The process is temporally dynamic, with complete transcytosis of IgA occurring in about 30 minutes in model epithelial systems.^[1] The final step entails docking and exocytosis at the opposing membrane, where vesicles fuse to release cargo extracellularly. This fusion is mediated by SNARE proteins, such as syntaxin-3 and SNAP-23 at the apical surface or syntaxin-4 at the basolateral, in an NSF-dependent manner that coordinates precise membrane insertion.^[1] In polarized cells, tight junctions and microtubule orientation maintain directional fidelity, preventing leakage.^[18]

Key Molecular Components

Transcytosis relies on specialized molecular components that facilitate the formation, trafficking, and fusion of vesicles across cellular barriers, particularly in endothelial and epithelial cells. Among these, caveolae represent a prominent structural feature involved in non-clathrin-mediated endocytosis. Caveolae are flask-shaped plasma membrane invaginations, typically 50-80 nm in diameter, formed by the oligomerization of caveolin proteins, which create cholesterol-rich domains essential for vesicle budding and transport. Caveolin-1 (Cav-1), the primary isoform in endothelial cells, is a 21-24 kDa integral membrane protein with a hydrophobic hairpin domain that inserts into the lipid bilayer, enabling it to scaffold caveolae formation and interact with signaling molecules and cargoes. Cav-1 interacts with cholesterol and sphingolipids to stabilize these structures, and its phosphorylation on tyrosine residues regulates caveolae dynamics during transcytosis. Caveolin-2 and caveolin-3 are accessory proteins; Cav-2 co-assembles with Cav-1 in non-muscle cells to modulate caveolae stability, while Cav-3 is muscle-specific and less involved in endothelial transcytosis. In brain endothelial cells, Cav-1 knockout disrupts caveolae-mediated transport of molecules like albumin and LDL, confirming its essential role in maintaining barrier permeability without lysosomal degradation. Recent studies as of 2025 have confirmed the dominant role of caveolar transcytosis mediated by Cav-1 in LDL transport across arterial endothelium.^[19]^[20]^[21]^[22] Receptors on the plasma membrane initiate ligand-specific transcytosis by binding cargoes and recruiting endocytic machinery. The transferrin receptor (TfR), a dimeric type II transmembrane glycoprotein, binds holo-transferrin to internalize iron-loaded complexes via receptor-mediated endocytosis, followed by sorting in early endosomes for basolateral exocytosis in polarized cells. TfR's extracellular domain features two homologous lobes that undergo pH-dependent conformational changes, releasing iron in acidic endosomes while recycling apo-transferrin; in blood-brain barrier (BBB) endothelial cells, monovalent TfR antibodies exploit this pathway for therapeutic delivery without lysosomal targeting. The polymeric immunoglobulin receptor (pIgR), a 90-120 kDa type I transmembrane protein expressed on epithelial cells, binds dimeric IgA (dIgA) or pentameric IgM via its extracellular Ig-like domains, facilitating their apical transcytosis and cleavage to release secretory IgA. pIgR's cytoplasmic tail contains tyrosine-based motifs for basolateral internalization and Rab11 recruitment, ensuring directional transport across mucosal barriers. In endothelial contexts, the LDL receptor (LDLR), a 160 kDa mosaic protein with ligand-binding repeats, mediates transcytosis of low-density lipoprotein (LDL) particles across arterial endothelium, bypassing degradation through caveolae-dependent or clathrin-independent routes. LDLR's interaction with LDL involves calcium-dependent binding, and its endocytosis is dynamin-sensitive in some vascular beds, contributing to lipid delivery without intracellular accumulation.^[23]^[24]^[25] Adaptors and coat proteins orchestrate vesicle formation and scission during transcytotic endocytosis. Clathrin, a 190 kDa triskelion-shaped protein, assembles into polyhedral lattices on the cytosolic face of the plasma membrane, driving the invagination of receptor-bound cargoes like TfR in clathrin-mediated endocytosis (CME), which accounts for a significant portion of transcytosis in endothelial cells. Clathrin interacts with adaptor protein 2 (AP-2), a heterotetrameric complex (α, β2, μ2, σ2 subunits) that bridges the membrane and clathrin, recognizing tyrosine- or dileucine-based sorting signals on receptors such as TfR and pIgR. AP-2's μ2 subunit binds cargo tails directly, while its α-appendage recruits accessory proteins for lattice assembly, ensuring efficient pit formation with ~100-200 clathrin molecules per vesicle. Dynamin, a 100 kDa GTPase, forms helical collars around vesicle necks, hydrolyzing GTP to constrict and sever clathrin-coated pits, releasing ~50-100 nm vesicles for transcytosis; in BBB endothelium, dynamin inhibition blocks TfR-mediated transport, highlighting its role in both clathrin- and caveolae-dependent pathways. These components collectively enable selective cargo uptake, as seen in the vesicular transport process where dynamin scission precedes Rab-mediated trafficking.^[26]^[3]^[27] Trafficking elements guide vesicles through intracellular compartments to their exocytic destinations. Rab GTPases, small monomeric GTP-binding proteins, cycle between GDP-bound inactive and GTP-bound active states to direct vesicle tethering and fusion; Rab11, localized to recycling endosomes, promotes the sorting and apical-to-basolateral transcytosis of cargoes like TfR and IgA by recruiting effectors such as Rab11-FIP2, which links vesicles to microtubules in polarized endothelial cells. Rab11's geranylgeranylation anchors it to membranes, and its activation facilitates tubule formation from early endosomes, preventing lysosomal diversion. SNARE proteins mediate membrane fusion during exocytosis; VAMP3 (vesicle-associated membrane protein 3, or cellubrevin), a 12 kDa v-SNARE on recycling vesicles, forms trans-SNARE complexes with plasma membrane t-SNAREs like syntaxin-4 and SNAP-23 to drive TfR vesicle fusion at the basolateral membrane in BBB endothelium. VAMP3's SNARE motif zipper-like assembly releases energy for bilayer mixing, underscoring its specificity for recycling pathways over bulk endocytosis. Depletion of VAMP3 reduces transcytotic efficiency. These elements ensure vectorial transport, integrating with receptor sorting for efficient macromolecule delivery. In lung endothelium, CXCR2 has emerged as a mediator of chemokine transcytosis across endothelial and epithelial barriers.^[28]^[29]^[30]^[31]

Regulation

Intracellular Pathways

The PI3K-Akt signaling pathway is a key intracellular regulator of transcytosis, primarily by facilitating endosomal trafficking while diverting cargo away from lysosomal degradation pathways. Upon activation, PI3K generates phosphatidylinositol-3,4,5-trisphosphate (PIP3), which recruits Akt to the plasma membrane, where it becomes phosphorylated and activated. This activation promotes the recruitment of effector proteins that enhance the motility and sorting of endocytic vesicles towards recycling or transcytotic compartments, thereby increasing the efficiency of transcytosis in epithelial and endothelial cells.^[32] In the context of polymeric immunoglobulin receptor (pIgR)-mediated transcytosis, PI3K-Akt signaling coordinates actin cytoskeleton reorganization, ensuring proper vesicle progression from early endosomes to the basolateral membrane.^[33] External ligands, such as growth factors, can initiate this pathway through receptor tyrosine kinases, linking upstream signals to intracellular control of transcytotic flux.00703-8.pdf) MAPK/ERK signaling further modulates transcytosis by controlling receptor recycling and vesicle fusion events, particularly in ligand-responsive systems. ERK1/2 activation, often downstream of receptor tyrosine kinases, leads to phosphorylation of Rab11-family interacting protein 5 (FIP5), a key effector in the Rab11 recycling pathway. This phosphorylation enhances the association of FIP5 with Rab11, promoting the directed transport of recycling endosomes and facilitating vesicle fusion at the target membrane during transcytosis.^[34] In pIgR transcytosis, this kinase cascade, involving Yes-Src and EGFR, ensures efficient apical-to-basolateral delivery of dimeric IgA by regulating the sorting and fusion steps at common recycling endosomes. Inhibition of ERK signaling disrupts these processes, leading to impaired receptor recycling and reduced transcytotic throughput.^[35] Calcium-dependent pathways, mediated by calmodulin and protein kinase C (PKC), are essential for the final exocytosis stage of transcytosis, particularly in docking and fusion of vesicles with the plasma membrane. Intracellular calcium elevations bind to calmodulin, inducing a conformational change that activates downstream targets involved in SNARE complex assembly and vesicle priming.62005-3/fulltext) Calmodulin antagonists like W-7 inhibit pIgR transcytosis by disrupting endosomal sorting and delivery, highlighting its role in maintaining the integrity of the transcytotic pathway.^[36] Similarly, PKC isoforms, activated by calcium and diacylglycerol, phosphorylate SNARE proteins and cytoskeletal elements to facilitate vesicle docking and membrane fusion during basolateral exocytosis in endothelial transcytosis.^[20] This dual regulation ensures precise temporal control, with PKC enhancing the efficiency of caveolae-mediated transcytosis under physiological conditions.^[19] Feedback loops involving autophagy-related proteins, such as LC3, provide adaptive modulation of transcytosis under cellular stress, particularly in endothelial cells. LC3 lipidation and incorporation into autophagosomal membranes can intersect with endocytic pathways, influencing vesicle fate by promoting selective autophagy of transcytotic components or cargo under high-glucose stress.^[37] In endothelial models, CAV1-CAVIN1-LC3B signaling drives autophagic degradation that regulates low-density lipoprotein (LDL) transcytosis, reducing excessive lipid transport across the blood-brain barrier during metabolic stress.^[38] Recent studies emphasize that LC3-mediated autophagy acts as a negative feedback mechanism, dampening transcytosis to prevent barrier dysfunction in inflammatory or hyperglycemic environments.^[39]

Environmental Influences

Ligand concentration plays a key role in modulating the rate and efficiency of transcytosis, particularly in mucosal epithelia where high levels of dimeric IgA can saturate the polymeric immunoglobulin receptor (pIgR), thereby upregulating the overall transcytotic flux across the epithelial barrier.^[40] In intestinal mucosa, elevated IgA concentrations promote increased pIgR-mediated transport, enhancing the delivery of secretory IgA to the luminal surface for immune defense, with the process showing dose-dependent kinetics up to receptor saturation.^[41] This mechanism ensures adaptive responses to varying antigen loads without altering receptor expression directly. pH and ionic gradients within endosomal compartments critically influence transcytosis by facilitating receptor-ligand dissociation, which directs cargo sorting toward transcytotic or recycling pathways. In early endosomes, the acidic milieu (pH ≈ 5.3–6.0) protonates ligands and receptors, promoting their separation for many receptor-mediated systems, such as transferrin or low-density lipoprotein (LDL) transport across endothelia.^[42] Ionic imbalances, including shifts in chloride or calcium concentrations, further stabilize these gradients, ensuring efficient vesicle maturation and preventing premature fusion with lysosomes, thus preserving cargo integrity during basolateral-to-apical or apical-to-basolateral transit.01570-5.pdf) In endothelial cells, shear stress exerted by blood flow dynamics modulates caveolae-mediated transcytosis, with physiological levels enhancing the formation and trafficking of caveolin-1-enriched vesicles that facilitate LDL permeation across the vascular barrier. Recent studies indicate that laminar shear stress downregulates caveolar dynamics, decreasing LDL transcytosis rates in arterial endothelia compared to disturbed flow, as observed in a 2022 study modeling fluid flow impacts on lipid transport.^[43] This mechanosensitive response adapts endothelial permeability to hemodynamic conditions, balancing nutrient delivery with barrier integrity. Hormonal signals, such as insulin, influence nutrient absorption in absorptive tissues like the intestine by promoting the activity and expression of glucose transporters such as SGLT1, thereby enhancing overall glucose uptake in response to postprandial cues.^[44] This hormonal modulation integrates systemic metabolic needs with local transport efficiency, often linking to downstream signaling pathways for fine-tuned regulation.^[45]

Physiological Roles

In Epithelial and Endothelial Barriers

Transcytosis is essential for maintaining selective permeability at the blood-brain barrier (BBB), where it enables the receptor-mediated transport of vital nutrients while preserving the barrier's tightness against nonspecific leakage. The transferrin receptor facilitates the endocytosis and transcytosis of iron-bound transferrin from the blood to the brain parenchyma, supplying iron for neuronal metabolism without compromising the integrity of tight junctions. Similarly, the insulin receptor mediates the transcytosis of insulin across BBB endothelial cells, supporting glucose uptake and energy homeostasis in the central nervous system.^[46] In the intestinal epithelium, transcytosis underpins mucosal immunity by directing the apical secretion of immunoglobulins. Dimeric IgA, secreted by plasma cells in the lamina propria, binds to the polymeric immunoglobulin receptor (pIgR) on the basolateral membrane of epithelial cells and undergoes transcytosis to the apical surface, where it is cleaved and released as secretory IgA to coat the gut lumen and neutralize pathogens. In neonates, the neonatal Fc receptor (FcRn) drives apical-to-basolateral transcytosis of maternal IgG from ingested milk across the intestinal epithelium, conferring passive immunity during early development.^[47]^[48] Across general endothelial barriers in capillaries, transcytosis of albumin via plasmalemmal vesicles allows controlled movement of this protein from the bloodstream to the interstitium, aiding in the maintenance of colloidal osmotic pressure and fluid balance. This vesicular pathway, observed in myocardial and other continuous endothelia, ensures that albumin transport occurs independently of paracellular routes, preserving vascular selectivity.^[49] In healthy epithelial and endothelial barriers, transcytosis contributes a small fraction to total flux, prioritizing specific macromolecular delivery over bulk permeation to uphold barrier function. This limited role, regulated by intracellular components such as those suppressing caveolae formation, underscores transcytosis's precision in nutrient supply and immune surveillance.^[3]

In Nutrient and Macromolecule Transport

Transcytosis plays a crucial role in iron homeostasis by facilitating the delivery of iron-bound transferrin across endothelial barriers to support cellular functions in protected compartments. In the blood-brain barrier (BBB), receptor-mediated transcytosis of transferrin-iron complexes occurs through brain capillary endothelial cells, where transferrin binds to transferrin receptor 1 (TfR1) on the luminal surface, is internalized via clathrin-coated vesicles, and is transported to the abluminal side for release into the brain parenchyma, thereby maintaining neural iron levels essential for neurotransmitter synthesis and myelin production.^[50] This process is saturable and energy-dependent, with studies demonstrating that holotransferrin (iron-loaded) is preferentially transcytosed compared to apotransferrin, ensuring efficient iron supply without compromising barrier integrity.^[4] Similarly, in the placenta, transferrin-mediated iron transport supports fetal development by enabling maternal iron delivery against a concentration gradient; this involves receptor-mediated endocytosis of transferrin-iron via TfR1 on the syncytiotrophoblast apical membrane, followed by release of iron into the cytoplasm and basal export via ferroportin, rather than classical vesicular transcytosis of the intact complex.^[51] Beyond iron, transcytosis contributes to lipid distribution, particularly through the transport of apolipoprotein B (ApoB)-containing low-density lipoproteins (LDL) across arterial endothelium, which delivers cholesterol to subendothelial tissues. In arterial walls, LDL particles bind to scavenger receptors or proteoglycans on endothelial cells, undergoing caveolae-mediated transcytosis to the intima, where accumulation promotes cholesterol homeostasis but can initiate atherogenesis if excessive.^[22] This process is regulated by endothelial lipid uptake pathways, with ApoB serving as the primary ligand, and quantitative models indicate that transcytotic flux rates correlate with plasma LDL levels, influencing systemic cholesterol partitioning.^[52] Representative in vitro studies using human aortic endothelial cells have shown directed LDL transcytosis, underscoring its role in nutrient delivery.^[53] The neonatal Fc receptor (FcRn)-mediated handling of immunoglobulin G (IgG) in endothelial cells extends IgG serum half-life through protective recycling, distinct from transcytosis. In vascular endothelium, IgG is internalized into endosomes at neutral pH, where it binds FcRn at acidic pH (~6.0), diverting it from lysosomal degradation back to the cell surface for re-release into circulation, thereby prolonging half-life to about 21 days compared to hours for non-FcRn-bound proteins.^[54] This recycling pathway maintains high IgG levels for immune surveillance, with mutations disrupting FcRn binding reducing half-life by over 80% in animal models.^[54] Efficiency varies by IgG subclass, with IgG1 showing optimal FcRn affinity for sustained transport.^[55] In maternal-fetal exchange, placental transcytosis is vital for transferring IgG and select nutrients, providing passive immunity and developmental support to the fetus. FcRn on syncytiotrophoblast cells mediates directional transcytosis of maternal IgG from the apical (maternal) to basal (fetal) side via vesicular trafficking, with peak transfer in the third trimester ensuring fetal IgG levels reach 100-120% of maternal concentrations for antimicrobial protection.^[56] This process involves pH-dependent binding in endosomes, similar to endothelial recycling, and is selective for IgG over other immunoglobulins. For nutrients, transcytotic mechanisms complement carrier-mediated transport; for instance, receptor-mediated vesicular pathways deliver macromolecules like vitamin B12-transferrin conjugates, though small nutrients like glucose primarily use facilitated diffusion—transcytosis here emphasizes macromolecular supply critical for fetal immunity and growth.^[57] Disruptions in FcRn expression reduce IgG transfer by up to 90%, highlighting its essentiality.^[58]

Role in Pathogenesis

In Vascular and Inflammatory Diseases

Dysregulated transcytosis in vascular endothelium contributes to the pathogenesis of various diseases by promoting excessive leakage of plasma components into tissues, exacerbating inflammation and tissue damage. In atherosclerosis, enhanced caveolae-mediated transcytosis of low-density lipoprotein (LDL) across endothelial cells facilitates subendothelial accumulation of lipids, a critical early event in plaque formation.^[59] Caveolin-1, the principal structural protein of caveolae, drives this process; its deficiency in mouse models reduces LDL transcytosis by up to threefold in aortic segments, thereby attenuating lesion development and foam cell formation from oxidized LDL uptake by macrophages.^[59] Recent evidence from 2025 underscores that pro-inflammatory factors like advanced glycation end-products (AGEs) and interleukin-1β amplify caveolin-1 expression via NF-κB signaling, increasing LDL flux and promoting foam cell-laden plaques.^[59] In kidney disease, elevated podocyte transcytosis disrupts the glomerular filtration barrier, leading to albuminuria as an early marker of renal dysfunction. Podocytes endocytose and transcytose albumin through caveolae and neonatal Fc receptor (FcRn) pathways, but in pathological states such as diabetic nephropathy, this process intensifies, with angiotensin II enhancing transport of up to 86% of endocytosed albumin to the urinary space.^[60] This abnormal transcytosis precedes structural barrier damage, increasing glomerular permeability and contributing to progressive proteinuric kidney injury.^[60] During systemic inflammation, such as in sepsis, cytokines and damage-associated molecular patterns induce endothelial transcytosis of plasma proteins, resulting in vascular leakage and edema formation. Lipopolysaccharide (LPS), a bacterial endotoxin that triggers cytokine release including TNF-α and IL-1β, phosphorylates caveolin-1 within hours, boosting albumin transcytosis across lung endothelium and causing protein-rich interstitial edema via the Starling principle.^[61] High mobility group box 1 (HMGB1), a pro-inflammatory mediator elevated in sepsis, further enhances this via the RAGE/Src/caveolin-1 axis, promoting hyperpermeability in inflamed vessels.^[62] In inflamed endothelium, transcytosis flux can increase up to 10-fold, amplifying tissue swelling and inflammatory cascades.^[63]

In Neurological and Barrier Dysfunction

In Alzheimer's disease (AD), the breakdown of the blood-brain barrier (BBB) is exacerbated by the transcytosis of amyloid-β (Aβ) peptides across endothelial cells via the receptor for advanced glycation end products (RAGE).^[64] This process facilitates the influx of circulating Aβ into the brain parenchyma, promoting the accumulation of amyloid plaques and contributing to neurodegeneration. Specifically, Aβ binding to RAGE on BBB endothelial cells triggers intracellular calcium influx and calcineurin signaling, which disrupts tight junctions such as claudin-5 and occludin, thereby increasing paracellular permeability alongside enhanced transcytosis.^[64] Experimental evidence from in vitro models of human brain microvascular endothelial cells demonstrates that RAGE inhibition reduces Aβ transcytosis by up to 60% and preserves BBB integrity, highlighting the receptor's central role in AD pathogenesis.^[64] Furthermore, multimodal RAGE inhibitors have been shown to limit Aβ-mediated brain influx and monocyte adhesion in mouse models of AD, underscoring the therapeutic potential of targeting this pathway to mitigate plaque exacerbation.^[65] Dysfunction of the blood-retina barrier (BRB) in retinopathies, such as diabetic retinopathy and age-related macular degeneration, involves heightened VEGF-driven transcytosis, leading to vascular leakage and retinal edema. Vascular endothelial growth factor (VEGF) upregulates plasmalemma vesicle-associated protein (PLVAP) in retinal endothelial cells, promoting caveolae-mediated vesicular transport that allows fluid and macromolecules to cross the barrier. A 2025 review synthesizes evidence from preclinical models, including oxygen-induced retinopathy in mice, where VEGF-induced PLVAP expression increases extravasation of 70 kDa tracers by enhancing transcytotic vesicles, without altering tight junctions.^[66] Inhibition of PLVAP or related pathways, such as P2X7 receptors, reduces this VEGF-mediated leakage by 40-50% in diabetic macular edema models, preserving BRB integrity and suggesting a shift from traditional anti-VEGF therapies to more targeted transcytosis modulators.^[67] In multiple sclerosis (MS), dysregulated transcytosis across the BBB enables the transport of inflammatory immune molecules, such as chemokines, into the central nervous system, fostering neuroinflammation and promoting demyelination. Upregulation of caveolae-mediated transcytosis in brain microvascular endothelial cells, driven by increased caveolin-1 expression, facilitates the shuttling of pro-inflammatory chemokines like CCL2 via the Duffy antigen receptor for chemokines (DARC), amplifying T-cell infiltration and microglial activation.^[68]^[69] This enhanced vesicular transport contributes to BBB leakiness, allowing immune mediators to reach oligodendrocytes and axons, thereby accelerating demyelination in active MS lesions. Studies in experimental autoimmune encephalomyelitis models, a proxy for MS, show that inhibiting caveolin-1 reduces chemokine transcytosis and attenuates demyelination severity by limiting immune cell diapedesis.^[69] HIV-1 neuroinfection relies on transcytosis across the BBB to establish viral reservoirs in the brain, bypassing immune surveillance and leading to chronic neuroinflammation. The virus, primarily in free or cell-associated forms, undergoes receptor-mediated endocytosis in endothelial cells, followed by vesicular trafficking to the abluminal side, with approximately 17% of inoculum crossing in vitro within 4 hours via gp160 envelope-dependent mechanisms.^[70] This process involves interactions with proteoglycans and mannose-6-phosphate receptors, enabling HIV-1 to infect perivascular macrophages and microglia without disrupting tight junctions. In humanized mouse models, HIV-1 transcytosis correlates with increased brain viral loads and cognitive impairment, emphasizing its role in HIV-associated neurocognitive disorders.^[70]

Clinical Applications

Drug Delivery Across Barriers

Transcytosis serves as a key mechanism for overcoming impermeable biological barriers, such as the blood-brain barrier (BBB), to enable targeted delivery of therapeutics that cannot passively diffuse. Strategies leveraging receptor-mediated transcytosis (RMT) bind ligands to endothelial receptors, triggering endocytosis and vesicular transport across the cell, while adsorptive transcytosis exploits electrostatic interactions for non-specific uptake. These approaches are particularly vital for delivering large molecules like monoclonal antibodies (mAbs) to the central nervous system (CNS), where the BBB restricts access in healthy states but can be exploited therapeutically.^[71] One prominent strategy targets the transferrin receptor (TfR), highly expressed on brain endothelial cells, using conjugated nanoparticles to ferry mAbs across the BBB for brain tumor treatment. TfR-conjugated liposomes or gold nanoparticles bind the receptor on the luminal surface, initiating clathrin-independent endocytosis and subsequent transcytosis to the abluminal side, allowing payload release into the brain parenchyma. For instance, low-affinity anti-TfR antibodies on gold nanoparticles achieved 0.23% injected dose per gram (ID/g) brain accumulation in mouse models, enabling targeted delivery of chemotherapeutic mAbs while minimizing peripheral off-target effects. This approach has shown nearly two-fold higher uptake in brain capillaries compared to non-targeted carriers, enhancing tumor-specific efficacy in preclinical studies.^[72]^[72]^[73] Nasal-to-brain delivery via adsorptive transcytosis offers a non-invasive alternative, particularly for Parkinson's disease therapeutics, by administering drugs through the olfactory epithelium to bypass the BBB. Polymeric micelles, such as those loaded with rotigotine, leverage positive surface charges or cell-penetrating peptides to promote electrostatic adsorption and paracellular transport along olfactory nerves, facilitating direct CNS entry. In rat models, rotigotine-encapsulated micelles in thermosensitive gels demonstrated significantly enhanced brain bioavailability compared to oral administration, improving motor function restoration with reduced systemic exposure. This route exploits natural transcytotic pathways in nasal epithelia, achieving up to several-fold higher striatal drug levels relevant for dopaminergic therapies.^[74]^[74]^[75] Overall, RMT-based strategies have demonstrated brain uptake improvements of up to 5-10 fold over non-targeted methods in select models, though absolute parenchymal delivery remains below 1% ID/g, underscoring the need for affinity optimization to enhance therapeutic indices. As of 2025, advancements include Phase III trials for TfR-targeted bispecific antibodies (e.g., for Alzheimer's disease), showing promising CNS penetration in human studies.^[72]^[76]^[77]^[78]

Therapeutic Modulation Strategies

Therapeutic modulation of transcytosis involves targeted interventions to either inhibit or enhance the process, aiming to mitigate disease progression by altering the transport of macromolecules across endothelial or epithelial barriers. Inhibitors primarily focus on reducing pathological transcytosis, such as that of low-density lipoprotein (LDL) in atherosclerosis, where excessive LDL entry into the arterial intima initiates plaque formation. Dynamin blockers, which disrupt dynamin-dependent endocytosis essential for caveolae-mediated transcytosis, have shown promise in preclinical models; for instance, Dyngo-4a at 30 μmol/L nearly eliminates LDL transcytosis in human coronary artery endothelial cells, while dynasore halves transcytosis of LDL-sized tracers in human aortic endothelial cells.^[22] Similarly, inhibition of caveolin-1, a key structural protein in caveolae, reduces endothelial permeability to LDL; genetic knockout of caveolin-1 in mice results in approximately 50% less LDL uptake in aortas, and pharmacological agents like statins decrease caveolin-1 expression by about 75% at 10 nmol/L concentrations.^[22] Anti-ALK1 antibodies, targeting activin receptor-like kinase 1 involved in LDL binding and transcytosis, reduce LDL transcytosis by around 50% and lesion area by 50% in LDL receptor-deficient mice, highlighting a potential antibody-based strategy.^[22] Enhancement strategies aim to prolong the half-life of therapeutic immunoglobulins in conditions like autoimmunity, where engineered interactions with the neonatal Fc receptor (FcRn) can extend IgG circulation without upregulating endogenous FcRn via gene therapy. FcRn binds IgG at acidic pH in endosomes, recycling it to extend serum half-life; modifications to the Fc region of therapeutic antibodies improve pH-dependent FcRn binding kinetics, dramatically prolonging half-life—for example, optimized variants achieve up to threefold extension compared to wild-type IgG in preclinical models.^[79] This approach is particularly relevant for autoimmunity treatments, where extended half-life of anti-pathogenic IgG (e.g., in rheumatoid arthritis or myasthenia gravis) enhances efficacy without broadly affecting endogenous autoantibodies, as opposed to FcRn blockade strategies that reduce pathogenic IgG levels.^[55] Although direct gene therapy for FcRn upregulation remains exploratory and lacks clinical validation, antibody engineering serves as a practical enhancer for transcytosis-mediated IgG recycling.^[79] Clinical trials have advanced modulation strategies, particularly for renal and ocular diseases linked to dysregulated transcytosis. In diabetic nephropathy, where albumin transcytosis across glomerular endothelial cells contributes to albuminuria, phosphoinositide 3-kinase (PI3K) pathway inhibition shows potential; preclinical data indicate that PI3K/AKT suppression reduces albumin endocytosis and transcytosis, alleviating proteinuria in models of diabetic kidney disease.^[80] For retinopathy, anti-vascular endothelial growth factor (anti-VEGF) therapies control VEGF-induced transcytosis and vascular leakage; intravitreal aflibercept (VEGF-trap) reduces endothelial barrier disruption in proliferative diabetic retinopathy models, with Phase III trials (e.g., VISTA and VIVID) demonstrating sustained visual acuity improvements through decreased macular edema via transcytosis modulation.^[81]^[82] Safety considerations in transcytosis modulation emphasize avoiding unintended barrier disruption, which could exacerbate leakage or inflammation. Inhibiting caveolae-mediated pathways, as with dynamin blockers, risks off-target effects on general endocytosis, potentially impairing nutrient transport or causing endothelial instability, as observed in caveolin-1 knockout models with altered vascular permeability.^[22] Enhancing FcRn interactions requires careful dosing to prevent excessive IgG accumulation, which might promote immune complex deposition in autoimmunity.^[55] In clinical contexts like anti-VEGF therapy, repeated intravitreal administration can lead to transient barrier weakening or fibrosis, necessitating monitoring for long-term endothelial integrity.^[66] Overall, balancing efficacy with barrier preservation involves preclinical validation of selectivity, as non-specific modulation may heighten risks of vascular dysfunction in diseases already involving pathogenic transcytosis.^[83]

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