Polyphenol-Reinforced Glycocalyx-Like Hydrogel Coating Induced Myocardial Regeneration and Immunomodulation.

Although minimally invasive interventional occluders can effectively seal heart defect tissue, they still have some limitations, including poor endothelial healing, intense inflammatory response, and thrombosis formation. Herein, a polyphenol-reinforced medicine/peptide glycocalyx-like coating was prepared on cardiac occluders. A coating consisting of carboxylated chitosan, epigallocatechin-3-gallate (EGCG), tanshinone IIA sulfonic sodium (TSS), and hyaluronic acid grafted with 3-aminophenylboronic acid was prepared. Subsequently, the mercaptopropionic acid-GGGGG-Arg-Glu-Asp-Val peptide was grafted by the thiol-ene "click" reaction. The coating showed good hydrophilicity and free radical-scavenging ability and could release EGCG-TSS. The results of biological experiments suggested that the coating could reduce thrombosis by promoting endothelialization, and promote myocardial repair by regulating the inflammatory response. The functions of regulating cardiomyocyte apoptosis and metabolism were confirmed, and the inflammatory regulatory functions of the coating were mainly dependent on the NF-kappa B and TNF signaling pathway.

Adhesion dynamics of Janus nanocarriers to endothelial cells: A dissipative particle dynamics study.

Janus nanocarriers (NCs) provide promising features in interfacial applications such as targeted drug delivery. Herein, we use dissipative particle dynamics simulations to study the adhesion dynamics of NCs with Janus ligand compositions to the endothelial cell as a function of a series of effects, such as the initial orientation, ligand density, shape, and size of Janus NCs. The Janus NCs, with its long axis parallel to the endothelial glycocalyx (EG) layer, has the best penetration depth due to its lower potential energy and the lowest shell entropy loss. Among different shapes of Janus NCs, both the potential energy and the EG entropy loss control the penetration. In fact, at the parallel orientations, Janus shapes with a robust mechanical strength and larger surface area at the EG/water interface can rotate and penetrate more efficiently. An increase in the ligand density of Janus NCs increases entropy losses of both the hydrophilic and the hydrophobic ligands and decreases the potential energy. Thus, for a specific Janus NCs, functionalizing with an appropriate ligand density would help driving forces prevail over barriers of penetration into the EG layer. For a particular ligand density, once the radius of the Janus NCs exceeds the appropriate size, barriers such as hydrophobic ligands and shell entropy losses are also reinforced significantly and surpass driving forces. Our observations reveal that entropy losses for hydrophobic ligands of Janus NCs and for the shell of NCs are decisive for the adhesion and penetration of Janus NCs to endothelial cells.

Organ-on-a-Chip Approach for Accelerating Blood-Brain Barrier Nanoshuttle Discovery.

Organ-on-a-chip, which recapitulates the dynamics of in vivo vasculature, has emerged as a promising platform for studying organ-specific vascular beds. However, its practical advantages in identifying vascular-targeted drug delivery systems (DDS) over traditional in vitro models remain underexplored. This study demonstrates the reliability and efficacy of the organ-on-a-chip in screening efficient DDS by comparing its performance with that of a conventional transwell, both designed to simulate the blood-brain barrier (BBB). The BBB nanoshuttles discovered through BBB Chip-based screening demonstrated superior functionality in vivo compared to those identified using transwell methods. This enhanced effectiveness is attributed to the BBB Chip's accurate replication of the structure and dynamics of the endothelial glycocalyx, a crucial protective layer within blood vessels, especially under shear stress. This capability of the BBB Chip has enabled the identification of molecular shuttles that efficiently exploit the endothelial glycocalyx, thereby enhancing transendothelial transport efficacy. Our findings suggest that organ-on-a-chip technology holds considerable promise for advancing research in vascular-targeted DDS due to its accurate simulation of molecular transport within endothelial systems.

Cationic Polysaccharides Bind to the Endothelial Cell Surface Extracellular Matrix Involving Heparan Sulfate.

Cationic polysaccharides have been extensively studied for drug delivery via the bloodstream, yet few have progressed to clinical use. Endothelial cells lining the blood vessel wall are coated in an anionic extracellular matrix called the glycocalyx. However, we do not fully comprehend the charged polysaccharide interactions with the glycocalyx. We reveal that the cationic polysaccharide poly(acetyl, arginyl) glucosamine (PAAG) exhibits the highest association with the endothelial glycocalyx, followed by dextran (neutral) and hyaluronan (anionic). Furthermore, we demonstrate that PAAG binds heparan sulfate (HS) within the glycocalyx, leading to intracellular accumulation. Using an in vitro glycocalyx model, we demonstrate a charge-based extent of association of polysaccharides with HS. Mechanistically, we observe that PAAG binding to HS occurs via a condensation reaction and functionally protects HS from degradation. Together, this study reveals the interplay between polysaccharide charge properties and interactions with the endothelial cell glycocalyx toward improved delivery system design and application.

Glycocalyx-Mimicking Nanoparticles with Differential Organ Selectivity for Drug Delivery and Therapy.

Organ-selective drug delivery is expected to maximize the efficacy of various therapeutic modalities while minimizing their systemic toxicity. Lipid nanoparticles and polymersomes can direct the organ-selective delivery of mRNAs or gene editing machineries, but their delivery is limited to mostly liver, spleen, and lung. A platform that enables delivery to these and other target organs is urgently needed. Here, a library of glycocalyx-mimicking nanoparticles (GlyNPs) comprising five randomly combined sugar moieties is generated, and direct in vivo library screening is used to identify GlyNPs with preferential biodistribution in liver, spleen, lung, kidneys, heart, and brain. Each organ-targeting GlyNP hit show cellular tropism within the organ. Liver, kidney, and spleen-targeting GlyNP hits equipped with therapeutics effectively can alleviate the symptoms of acetaminophen-induced liver injury, cisplatin-induced kidney injury, and immune thrombocytopenia in mice, respectively. Furthermore, the differential organ targeting of GlyNP hits is influenced not by the protein corona but by the sugar moieties displayed on their surface. It is envisioned that the GlyNP-based platform may enable the organ- and cell-targeted delivery of therapeutic cargoes.

Importancia médica del glucocáliz endotelial: Parte 2: su papel en enfermedades vasculares y complicaciones de la diabetes mellitus / Medical significance of endothelial glycocalyx: Part 2: Its role in vascular diseases and in diabetic complications

El glucocáliz endotelial es una capa constituida por glucosaminoglicanos, proteoglicanos y glucoproteínas que cubre al endotelio en su cara luminal. La participación del deterioro del glucocáliz endotelial parece esencial en los pasos iniciales de la fisiopatología de la aterosclerosis, de las complicaciones microangiopáticas de la diabetes mellitus y de la enfermedad venosa crónica. Los factores de riesgo de la aterosclerosis como la hipercolesterolemia, la hiperglucemia, la inflamación, el exceso de sodio y las fuerzas de tensión alteradas causan deterioro del glucocáliz. Esto provoca disfunción endotelial y permite la filtración de lipoproteínas (LDL) y de leucocitos al espacio subendotelial, iniciando la formación de la placa de ateroma. En la diabetes el glucocáliz adelgazado, principalmente por estrés oxidativo, posibilita la filtración de proteínas (albuminuria) y el trastorno endotelial de la microangiopatía. La hipertensión venosa crónica altera las fuerzas de tensión y daña el glucocáliz, lo que permite la filtración de leucocitos a las partes más profundas de la pared venosa, iniciando la inflamación y el deterioro morfológico y funcional de las venas que lleva a la enfermedad venosa crónica. El tratamiento con glucosaminoglicanos (sulodexida) logra prevenir o revertir el daño al glucocáliz endotelial y algunas de sus consecuencias; es eficaz en la enfermedad venosa crónica, especialmente con úlceras venosas. También ha sido útil en aterosclerosis obliterante de miembros inferiores y en la nefropatía diabética con albuminuria.

Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. Shredding of glycocalyx appears as an essential initial step in the pathophysiology of atherosclerosis and microangiopathic complications of diabetes mellitus, as well as in chronic venous disease. Atherosclerosis risk factors, as hypercholesterolemia (LDL), hyperglycemia, inflammation, salt excess and altered shear stress can damage glycocalyx. This lead to endothelial dysfunction and allows LDL and leukocytes to filtrate to the subendothelial space initiating atheroma plaque formation. Degradation of glycocalyx in diabetes mellitus is mainly due to oxidative stress and enables protein filtration (albuminuria) and endothelial disorder of microangiopathy. Chronic venous hypertension brings to altered shears stress which results in shredded glycocalyx, this allows leukocytes to migrate into venous wall and initiate inflammation leading to morphologic and functional venous changes of the chronic venous disease. Treatment with glycosaminoglycans (sulodexide) prevents or recovers the damaged glycocalyx and several of its consequences. This drug improves chronic venous disease and promotes healing of chronic venous ulcers. It has also been useful in peripheral arterial obstructive disease and in diabetic nephropathy with albuminuria.