Nanocarriers for targeted drug delivery in the vascular system: focus on endothelium

Abstract

Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the vascular system, particularly targeting ECs for therapeutic purposes. However, the complex interactions between vascular ECs and nanocarriers present significant challenges for the development and clinical translation of nanotherapeutics. This review assesses recent advancements and key strategies in employing nanocarriers for drug delivery to vascular ECs. It suggested that through precise physicochemical design and surface modifications, nanocarriers can enhance targeting specificity and improve drug internalization efficiency in ECs. Additionally, we elaborated on the applications of nanocarriers specifically designed for targeting ECs in the treatment of cardiovascular diseases, cancer metastasis, and inflammatory disorders. Despite these advancements, safety concerns, the complexity of in vivo processes, and the challenge of achieving subcellular drug delivery remain significant obstacles to the effective targeting of ECs with nanocarriers. A comprehensive understanding of endothelial cell biology and its interaction with nanocarriers is crucial for realizing the full potential of targeted drug delivery systems.

Keywords: Drug delivery; Drug targeting; Nanocarriers; Nanomedicine; Vascular endothelial cells.

Fig. 1

Successful strategies of nanotechnology to overcome biological obstacles. Recent advances in the use of nanotechnology to overcome four major biological barriers, including lung mucus, gastrointestinal mucus, placental barrier, and BBB [12]

Fig. 2

Physiological characteristics and functions of ECs. A The general structure of blood vessels [61]. B The endothelium provides an extremely large surface area for drug delivery [9]. C The endothelium under physiologic conditions. D Dysfunctional ECs often exhibit elevated levels of inflammation-related adhesion molecules, such as VCAM-1, ICAM-1, P-selectin, and E-selectin, which can contribute to cardiac dysfunction. A reduction in the production of the anticoagulant protein TM by endothelial cells can promote thrombosis induced by hemagglutination. Furthermore, reduced production of NO may lead to inflammation and elevated blood pressure, potentially facilitating the development of atherosclerosis

Fig. 3

The vascular endothelium: a victim, barrier, and target of drug delivery. A Drug delivery system (DDS) therapy faces intravascular barriers such as intravascular enzymatic degradation and sequestration of the MPS. B In drug delivery strategies requiring cargoes to be released or act in the bloodstream, such as long-circulating reactors or slow-release systems, respectively, nanocarrier interaction with endothelium must be avoided. Otherwise, nanocarriers’ adherence to endothelium may lead to vascular occlusion, endothelial damage, or pathological activation. C For the paracellular pathway, nanocarriers transport passively through gaps in the endothelium. These intercellular gaps result from the abnormal vessel structures caused by rapid tumor angiogenesis and are fundamental for the EPR effect. For transcellular pathways, nanocarriers get transported actively into the tumor microenvironment via intracellular vesicles or through transcellular pores. D In strategies targeting drug nanocarriers to the endothelial surface determinants, ligand-mediated anchoring may result in surface retention or internalization [3, 17, 78]

Fig. 4

Nanocarriers for vascular delivery. Nanocarriers smaller than 10 nm tend to be cleared by the kidney from circulation or extravasate into tissue. Nanocarriers with dimensions smaller than 10 nm are generally cleared by the kidneys from circulation or extravasate into surrounding tissues. Nanocarriers ranging from 20 to 200 nm predominantly undergo clearance via the RES, whereas nanocarriers exceeding 500 nm are typically trapped within the microvasculature. Spherical nanocarriers within the range of 50–300 nm exhibit prolonged circulation times, as they can circumvent sequestration by the kidneys and liver while being sufficiently small to evade splenic filtration [30]

Fig. 5

Common uptake pathways that ultimately determine nanocarrier fate within a cell. A Upon interaction with the cell surface, nanocarrier—depending on their surface, size, shape and charge—are taken up by various types of endocytosis or pinocytosis via non-specific interactions, such as membrane wrapping, or specific interactions, such as with cell surface receptors. B Once they have entered the cell, nanocarriers remain trapped within vesicular compartments, or endosomes, that feature various characteristics such as internal or external receptors. To achieve functional delivery, most nanocarriers must escape from these compartments before they acidify. Thus, responsive nanocarriers—such as ionizable nanocarriers that become charged in low-pH environments—aid in endosomal escape and allow for intracellular delivery whereas unresponsive nanocarriers often remain trapped and are destroyed by lysosome acidity and proteolytic enzymes [2]

Fig. 6

Mechanisms of nanocarriers targeting. A Passive targeting depends on the physicochemical properties of nanocarriers, including size, shape, rigidity, and surface charge, to interact optimally with anatomical and physiological environments, thus facilitating their transport to specific organs without necessitating surface ligand modification. B Active targeting involves the modification of nanocarrier surfaces with ligands or antibodies that bind to overexpressed receptors on target cells, thereby enabling the precise delivery of therapeutic payloads. C Endogenous targeting requires the design of nanocarriers that bind to various subgroups of plasma proteins upon injection, thereby directing these nanocarriers to target organs and facilitating their uptake by specific cells [18]

Fig. 7

Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the BBB. A Three-dimensional reconstructions and average intensity projections of SPECT (red) and CT (gray) signals were obtained for intrastriatal TNF-α-injured mice administered IgG or anti–VCAM-1 functionalized liposomes. B VCAM-targeted lipid nanoparticles (LNPs) elicited significantly higher levels of mean fluorescence intensity in liposome-positive ECs compared to control and TNF-α-injured mice. C The cerebral uptake of radiolabeled anti-VCAM/LNP was over tenfold greater than that of IgG/LNP in control mice and more than 70-fold greater in TNF-α-challenged mice. D VCAM-1-targeted liposomal nanoparticles, loaded with mRNA encoding TM, effectively targeted the brain vascular endothelium and delivered genes to mitigate TNF-α-induced acute brain inflammation in a murine model [111]

Fig. 8

Functional platesomes (Fe@PLP-TR-A) enhanced endothelial barrier preservation against MI reperfusion injury. Schematic illustration of (A) fabrication of Fe@PLP-TR-A and (B) the targeting ability and mechanism of Fe@PLP-TR-A for protection of endothelial barrier. (1) Targeting of Fe@PLP-TR-A to the damaged endothelium via platelets membrane proteins. (2) Extracellular release of ANGPTL4 via cleavage of specific peptide by thrombin and maintenance of VE-Cadherin. (3) Intracellular release of Fe₃O₄ through endosome escape and scavenge of H₂O₂ to protect endothelial cells from apoptosis [117]

Fig. 9

The physicochemical properties of the nanocarriers determine the distribution and clearance of drugs. Spherical and larger nanocarriers marginate more easily during circulation, whereas rod-shaped nanocarriers extravasate more readily (top left); and uncoated or positively charged nanocarriers are cleared more quickly by macrophages (top right). In terms of local distribution, in general, rod-shaped, neutral and targeted nanocarriers penetrate tumors more readily (bottom left) whereas positively charged, smaller and coated nanocarriers more easily traverse mucosal barriers (bottom right) [2]

Fig. 10

Cationization-initiated transcytosis-mediated active tumor penetration for the transendothelial and transcellular transport of nanomedicine. (1) The neutral long-circulating nanomedicine is converted into a cationic form by enzymes on the luminal surface of ECs, thereby initiating adsorption-mediated transcytosis (AMT) across the endothelium. (2) Nanomedicine may also extravasate through the permeable blood vessel wall into the tumor interstitium, a process associated with the EPR effect, where enzymes on tumor cell surfaces catalyze its cationization for AMT. (3) Active tumor penetration is achieved through cancer-cell transcytosis of nanomedicine. (4) Cationic nanomedicine is rapidly internalized by cancer cells via AMT, some of the nanomedicine is intracellularly transferred and subsequently exocytosed into the interstitium, where it is then internalized by adjacent cells and transferred to deeper layers, thereby facilitating deep penetration into tumor tissues [23]

Fig. 11

Genetically engineered cell membrane–coated nanoparticles for targeted drug delivery to inflamed lungs. Wild-type cells were genetically engineered to express VLA-4, which is composed of integrins α4 and β1. Then, the plasma membrane from the genetically engineered cells was collected and coated onto dexamethasone-loaded nanoparticle cores (DEX-NP). The resulting VLA-4–expressing cell membrane–coated DEX-NP (VLA-DEX-NP) can target VCAM-1 on inflamed lung ECs for enhanced drug delivery [172]

Fig. 12

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo. A The unsupervised hierarchical clustering of the RNA-seq data showed a clear demarcation of between disturbed blood flow (DF)- and unidirectional flow (UF)-exposed human aortic ECs. TXNDC5, along with atherogenic factors including CXCR4 and NOX4 were significantly up-regulated. B En face staining of the mouse aorta showed increased TXNDC5 expression in the endothelium of aortic arch (AA) compared to the descending thoracic aorta (DA) in C57BL/6 mice. C Reanalysis of microarray datasets obtained that TXNDC5 was significantly up-regulated in human atherosclerotic arteries (compared to healthy arteries) and in advanced atherosclerotic plaques (compared to early plaques). D Treatment with nanoparticles encapsulating CDH5-Cas9/sgRNA-Txndc5 significantly reduced carotid atherosclerosis in ApoE⁻/⁻ mice. E Schematic summary of the proposed molecular mechanisms by which mechanosensitive TXNDC5 contributes to endothelial activation and atherosclerosis induced by DF, which can be targeted by nanomedicine-mediated genome editing [174]

Fig. 13

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain. A α-ICAM rapidly accumulate in the lungs and then migrate to the brain. Lung and brain pharmacokinetics of mAbs directed against ICAM following IV injection 2 h post-TNF-α injury. B Histology of brain tissue sections collected 22 h postinjection of polystyrene nanoparticles in TNF-α challenged mice. Nanocarriers association with ECs (VCAM) was measured for IgG nanoparticles and ICAM-targeted. C ICAM-targeted dexamethasone (Dex) liposomes protect mice from TNF-induced brain edema. D Schematic illustration of targeted nanocarriers co-opting pulmonary intravascular leukocytes for drug delivery to the injured brain [182]