---
title: "Targeting angiogenesis with nanobodies: article unavailable — source details and expected scope"
id: "frontiers-in-immunology-16-targeting-angiogenesis-advances-in-the-design-and-engineered-applications-of"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-targeting-angiogenesis-advances-in-the-design-and-engineered-applications-of"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1912560"
published_at: "2026-08-21T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Targeting angiogenesis with nanobodies: article unavailable — source details and expected scope
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-targeting-angiogenesis-advances-in-the-design-and-engineered-applications-of
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1912560)
- **Published At:** 2026-08-21T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source content from Frontiers in Immunology contains site navigation, journal metadata, and repeated header material but does not include the article text or abstract for “Targeting angiogenesis: advances in the design and engineered applications of nanobodies.” - Key bibliographic elements (full abstract, methods, results, conclusions, figures, author list) were not present in the supplied source. Therefore specific study findings, experimental details, and conclusions cannot be summarized from this input. - The title indicates the article would address **angiogenesis** and engineered **nanobodies**, but no article body was provided to confirm scope, targets, or applications; any detailed claims about content would be speculative and therefore were not made. - Expected topics that the full article might cover (based only on the title) include nanobody design strategies, molecular targets involved in angiogenesis, engineered delivery formats, and potential preclinical or translational applications; these were not reported in the supplied source and are noted as expectations only. - Because the source lacks the article text, readers should consult the original Frontiers in Immunology webpage or the DOI link for the complete paper to obtain verified data, figures, and author-contributed conclusions. - The supplied material prevents extraction of metrics important for clinical or research appraisal (sample size, experimental models, efficacy endpoints, safety data, or specific molecular targets). - This summary documents the absence of primary article content in the provided source and lists suggested next steps to access the complete article for clinical or scientific use. Bolded terms highlight the central topics from the article title only: **angiogenesis**, **nanobodies**.
## Clinical Analysis & Structured Key Points
Frontiers | Targeting angiogenesis: advances in the design and engineered applications of nanobodies REVIEW article Front. Immunol. , 21 August 2026 Sec. Vaccines and Molecular Therapeutics Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1912560 Published in Frontiers in Immunology Vaccines and Molecular Therapeutics 7 impact factor 11.3 citescore Part of a Research Topic Nanobodies in Biomedical Research and Clinical Applications Submission open 2729 views 2 articles Editor & Reviewers Edited by J B Jamie Berta Spangler Reviewed by B J Babak Jahangiri X S XuXin Sun Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Figure 8 View in article Table 1 Common angiogenesis-dependent diseases and pathological mechanism. View in article Table 2 Overview of nanobodies targeting angiogenesis-related factors by targets. View in article Table 3 Current clinical development landscape of angiogenesis-related nanobody therapeutics and molecular imaging probes. View in article REVIEW article Front. Immunol. , 21 August 2026 Sec. Vaccines and Molecular Therapeutics Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1912560 Targeting angiogenesis: advances in the design and engineered applications of nanobodies Y L Yuxuan Liu 1,2 Z L Zhaohai Li 1 Y M Yuanyuan Ma 1 Y L Yulin Liu 1 * 1. No.2 Research Laboratory, Changchun Institute of Biological Products, Changchun, Jilin, China 2. School of Engineering, China Pharmaceutical University, Nanjing, Jiangsu, China Article metrics View details Abstract Angiogenesis is a fundamental physiological process; however, its pathological dysregulation drives diseases such as solid tumors, wet age-related macular degeneration, and rheumatoid arthritis. Although clinically effective, conventional anti-angiogenic monoclonal antibodies are limited by poor tissue penetration, off-target toxicities, and susceptibility to compensatory resistance. This review systematically examines the structural advantages and engineering strategies of nanobodies (Nbs) targeting angiogenesis-related pathways. Advanced engineering approaches, such as AI-assisted humanization and multivalent assembly, effectively mitigate immunogenicity and extend serum half-life. Furthermore, multispecific designs can simultaneously block compensatory pathways to circumvent resistance. Moreover, preclinical studies indicate that integrating these molecules into site-specific nanobody-drug conjugates and targeted delivery vehicles may improve therapeutic precision and local drug accumulation; however, their long-term safety, manufacturability, and clinical benefit remain to be established. Functionalizing Nbs with radionuclides or fluorophores may enable the development of novel theranostic platforms that support real-time molecular imaging and image-guided surgery. In parallel, nanobody-based CAR-T (Nb-CAR-T) cells facilitate the targeted remodeling of the disease microenvironment. Ultimately, this review highlights the value of engineered Nbs as a highly programmable and transformative platform. By overcoming key limitations of conventional antibodies, engineered nanobodies open new avenues for precise, multi-dimensional interventions in solid tumors. Their potential in certain non-neoplastic angiogenic diseases is emerging but requires further validation. 1 Introduction Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is a critical mechanism for maintaining organismal homeostasis and tissue repair. Although indispensable for biological events such as embryonic development, tissue growth, and wound healing, this process requires strict spatiotemporal regulation. Its persistent, aberrant activation serves as a common driver for numerous angiogenesis-dependent diseases, including solid tumors, wet age-related macular degeneration (wAMD), diabetic macular edema (DME), and rheumatoid arthritis ( 1 , 2 ) ( Table 1 ). Table 1 Disease category Related diseases Pathological features and angiogenesis mechanisms Malignant Tumors Colorectal cancer, Non-small cell lung cancer, Hepatocellular carcinoma, Glioblastoma Hypoxia in the tumor microenvironment induces overexpression of vascular endothelial growth factor(VEGF), driving abnormal angiogenesis to supply nutrients and promote metastasis ( 3 – 5 ). Ocular Diseases Wet age-related macular degeneration (wAMD), Diabetic macular edema (DME) Abnormal leakage and hemorrhage of choroidal/retinal neovascularization lead to photoreceptor damage and vision loss ( 6 , 7 ). Chronic Inflammation Rheumatoid arthritis (RA), Psoriasis Vasculature formation in synovial tissue, inflammatory cell infiltration, and increased vascular permeability cause tissue swelling and destruction ( 8 , 9 ). Fibrotic Diseases Idiopathic pulmonary fibrosis, Liver fibrosis Abnormal communication between blood vessels and stromal cells promotes fibroblast activation and extracellular matrix (ECM) deposition ( 10 , 11 ). Vascular Malformations Infantile hemangioma, Arteriovenous malformation Abnormal proliferation of local vascular endothelial cells, high expression of Glucose Transporter 1 and other markers, forming nodular vascular hyperplasia ( 12 – 14 ). Common angiogenesis-dependent diseases and pathological mechanism. In this regard, anti-angiogenic therapy has emerged as a hotspot for drug research and development over the past three decades. Traditional monoclonal antibodies, represented by bevacizumab and cetuximab, have achieved significant clinical success owing to their high specificity and potent neutralizing capabilities. However, these agents exhibit several clinical limitations. Their large molecular weight (~150 kDa) severely restricts penetration into solid tumors. Additionally, Fragment crystallizable(Fc)-mediated effector functions and prolonged serum half-lives elevate the risks of off-target toxicity and immunogenicity ( 15 ). Furthermore, single-target blockade often induces compensatory bypass activation, culminating in acquired drug resistance ( 16 ). Consequently, developing novel anti-angiogenic therapeutics that combine high affinity, superior tissue penetrability, and low immunogenicity remains an urgent clinical priority. Derived from camelid heavy-chain antibodies, nanobodies have emerged as promising candidates for next-generation targeted therapeutics due to their high solubility and modularity. Despite their compact size, they retain full antigen-binding capacity while exhibiting excellent tissue penetrability, rapid renal clearance, and robust stability. These features allow them to overcome the inherent limitations of traditional monoclonal antibodies, such as poor delivery efficiency and high immunogenicity, underscoring their strong potential for clinical translation ( 17 – 19 ). This review systematically examines the engineering strategies of anti-angiogenic nanobodies for translational applications. Furthermore, it highlights recent advances in humanization, multivalent and multispecific designs, targeted drug delivery, and theranostic platforms, concluding with a discussion of current challenges and future perspectives. 2 Structure and properties of nanobodies In addition to the conventional heterotetrameric antibodies, camelids possess a unique class of serum antibodies known as heavy-chain antibodies (HCAbs), a type of Immunoglobulin G(IgG) that naturally lacks light chains. At its N-terminal region, the H chain of the homodimeric protein contains a dedicated variable domain, referred to as Variable Heavy-chain domain of Heavy-chain antibodies (VHH), which is the structural and functional equivalent of the fragment antigen-binding (Fab) of conventional antibodies ( Figure 1A ). VHH typically has a molecular weight of 12–15 kDa and dimensions of approximately 4 × 2.5 × 3 nm, meanwhile, the compact architecture of VHH enables the rational size engineering across a wide spectrum, ranging from a few nanometers for monomers to over 10 nm when formatted as multivalent constructs or conjugated to therapeutic payloads, largely dictated by the dimensions of the conjugated moieties ( 20 ). Structurally, VHH comprises four conserved framework regions (FR1–FR4) and three complementarity-determining regions (CDR1-3) ( 21 ). To compensate for the lack of a variable light chain (VL), the VHH CDR3 is significantly elongated (16–18 residues). This extended loop forms a protruding, “finger-like” structure capable of penetrating deep into antigen clefts or cryptic epitopes ( 22 ). Additionally, substituting key hydrophobic residues in the FR2 region with hydrophilic ones (e.g., F/Y42, E49, R50, and G52) markedly improves their solubility and prevents aggregation ( 23 ). Furthermore, an extra disulfide bond is often present, which enhances conformational stability and rigidity ( 24 , 25 ). Consequently, VHH exhibits numerous advantages over full-length IgGs and traditional antibody fragments (e.g., scFv and Fab). Their high thermal stability, broad pH tolerance, high solubility, and low aggregation propensity facilitate long-term storage and administration. Moreover, their small size enhances penetration into dense tissues, such as solid tumors, while the absence of an Fc domain minimizes immunogenicity ( 26 – 28 ). VHHs with specific antigen-binding activity are isolated via library construction and display panning. Owing to their nanoscale size, these recombinant proteins are broadly known as nanobodies(Nbs) in downstream applications. Figure 1 (A) Comparison of the monoclonal antibody (mAb) vs. heavy chain antibody (HcAb) to highlight the structural differences of their respective antigen binding regions. The VHH has a much longer CDR3 loop compared to that of the VH-VL domains in mAbs, providing antigen affinity and access to hidden epitopes. (B) A generalized overview of the types of engineered nanobodies to demonstrate how their high modularity enables various modifications. These characteristics of VHH endow Nbs with a highly modular structure, facilitating the implementation of various engineering strategies ( Figure 1B ). For instance, multivalent or bispecific constructs can be readily generated using flexible linkers ( 29 , 30 ). Additionally, Nb functionality can be expanded by fusing them with effector molecules, such as drugs, therapeutic proteins, or imaging agents ( 17 , 31 ). These modular designs greatly simplify the assembly of multifunctional molecules, facilitating their broad application in disease diagnosis, targeted therapy, and drug delivery. In summary, Nbs engineering is spearheading a new paradigm in cancer therapy while demonstrating profound potential for targeted interventions in other angiogenesis-dependent diseases. 3 Angiogenesis and immunological regulation in the tumor microenvironment 3.1 Angiogenesis mechanisms and molecular targets The regulation of the angiogenesis involves a highly complex network of signaling pathways ( 2 , 32 , 33 ) ( Figure 2 ). The VEGF/VEGFR axis acts as the primary driver of angiogenesis, activating downstream cascades such as PI3K/AKT and MAPK/extracellular signal-regulated kinase(ERK) to promote endothelial cell proliferation, migration, tube formation, and vascular permeability ( 34 ). Concurrently, the Angiopoietin-2/Tie2(Ang2/Tie2) and Notch/DLL4 pathways govern vascular maturation and maintain orderly branching ( 35 ). Additionally, the PDGF/PDGFR, FGF/FGFR, and HGF/c-Met pathways are crucial for pericyte recruitment, endothelial cell survival, and compensatory signaling following VEGF blockade ( 36 ). Furthermore, under hypoxic conditions, the HIF-1α-mediated transcriptional network upregulates various pro-angiogenic factors, acting as a critical microenvironmental regulator of this process ( 37 ). Figure 2 Schematic diagram of the signaling pathway network during angiogenesis. Solid arrows indicate activation; blunt arrows indicate inhibition. Various biomolecules associated with these pathways—primarily pro-angiogenic factors, cell adhesion molecules, and microenvironmental regulators—serve as critical targets for nanobodies development ( Table 2 ) ( 32 ). Among these, pro-angiogenic factors (e.g., VEGF, FGF, angiopoietin, HGF, and their receptors) remain the primary focus of current nanobodies research. As extracellular proteins or membrane-bound receptors, these targets are highly accessible for nanobodies binding, enabling the efficient blockade of downstream signaling cascades. Furthermore, nanobodies targeting cell adhesion molecules (e.g., integrins and cadherins) and microenvironmental regulators (e.g., matrix metalloproteinases and HIF-1α) offer dual clinical and diagnostic advantages. They can be co-administered with anti-angiogenic therapies to enhance efficacy and mitigate drug resistance, while simultaneously serving as novel molecular tools for real-time imaging and precise evaluation of angiogenesis ( 38 , 39 ). Table 2 Nanobody target Core biological mechanism Model system Outcomes References VEGF-A (VEGF165) Binds to VEGFR-2 to activate PI3K/AKT and MAPK/ERK pathways, promoting endothelial cell (EC) proliferation, migration, tube formation, and vascular permeability. Chick chorioallantoic membrane (CAM) assay; Human Umbilical Vein Endothelial Cells (HUVECs)proliferation/tube formation assay. VA12 exhibits significant in vivo anti-angiogenic activity; the anti-VEGF nanobody dose-dependently inhibits HUVEC proliferation and tube formation. ( 40 , 41 ) VEGFR-2 The primary receptor for VEGF, mediating EC proliferation, migration, survival, and tube formation. HUVEC proliferation/tube formation assay; mouse pharmacokinetics (BALB/c). Specifically binds to cell-surface VEGFR-2; almost completely inhibits HUVEC tube formation in vitro . ( 42 , 43 ) Ang2 (Angiopoietin-2) Binds to Tie2 to destabilize blood vessels, acting synergistically with VEGF to promote neovascularization; it is highly upregulated in tumors. Phase Ib clinical trial (NCT03468426) enrolling patients with advanced solid tumors (e.g., Non-small cell lung cancer, metastatic Non-small cell lung cancer, Small cell lung cancer, melanoma, recurrent glioblastoma, hepatocellular carcinoma); mouse malignant glioma models (U87 MG, etc.). BI 836880 monotherapy is 720 mg IV Q3W; exhibits manageable safety and preliminary antitumor activity when combined with BI 754091; Ang2/VEGF-A bispecific antibody monotherapy or in combination with chemotherapy demonstrates the most robust vascular normalization. ( 44 , 45 ) HGF (Hepatocyte Growth Factor) Binds to c-Met to activate the PI3K/AKT pathway, promoting EC survival, migration, and compensatory angiogenesis. Nude mouse U87 MG glioblastoma xenograft model (biodistribution, 89Zr-Positron Emission Tomography(PET). Blocks HGF/c-Met interaction, inhibiting cellular signaling and proliferation; demonstrates high tumor-targeting selectivity and prolonged blood exposure following 89 Zr labeling; tumor growth is delayed or cured in the 100 μg dose group. ( 46 ) PLGF (Placental Growth Factor) Binds to VEGFR-1, synergizing with VEGF to enhance angiogenesis and vascular permeability. HUVEC MTT proliferation, 3D collagen tube formation, and MCF-7 migration assays; CAM model. The bivalent nanobody binds to PLGF with high affinity; significantly inhibits HUVEC proliferation, 3D tube formation, and MCF-7 migration; angiogenesis is suppressed in the CAM model. ( 47 – 49 ) NRP-1 (Neuropilin-1, co-receptor) Enhances VEGF-VEGFR-2 signaling, promoting EC migration and the recruitment of tumor-associated macrophages. HUVEC MTT proliferation assay, Matrigel tube formation assay, CAM model, nude mouse HCT116 colon cancer xenograft model. Enhances angiogenesis inhibition when combined with anti-VEGF therapy; significantly reduces tumor volume and weight in mouse models; high-affinity NRP-1 nanobody inhibits HUVEC proliferation, tube formation, and CAM angiogenesis. ( 50 – 52 ) DLL4 (Delta-like ligand 4) A Notch ligand that regulates tip/stalk cell differentiation, preventing excessive vascular branching. MKN cell MTT proliferation and Annexin V/PI apoptosis assays; chick CAM model. DLL4 nanobody 3Nb3 binds to and is internalized by MKN cells; it dose-dependently inhibits proliferation and induces apoptosis; it induces abnormal/non-functional angiogenesis in the CAM model. ( 53 , 54 ) PDGF-B Binds to PDGFR-β, recruiting pericytes to cover newly formed blood vessels and maintaining vascular stability. None CD105 (Endoglin, TGF-β co-receptor) A specific marker for tumor neovascular ECs, promoting angiogenesis and pericyte recruitment. HUVEC counting/MTT proliferation assay, fibrin gel tube formation assay. Achieved high-affinity HUVEC-specific nanobody AR-86a; significantly inhibits HUVEC proliferation and capillary-like structure formation. ( 55 ) Integrin αvβ3/αvβ5 Mediates EC adhesion to the ECM, activates focal adhesion kinase/Src proto-oncogene tyrosine kinase signaling pathway, and promotes EC migration, survival, and vasculogenic mimicry. MTT assay, SKOV3 xenograft mouse model. The nanobody-drug conjugate exhibits superior targeting, cellular uptake, and cytotoxicity; demonstrates long-term in vivo retention and high tumor accumulation. ( 39 ) VE-cadherin (Vascular endothelial cadherin) Maintains stable junctions between ECs, regulating vascular permeability and lumen assembly. None CD93 (Endothelial cell surface receptor) Participates in EC adhesion, vascular permeability regulation, and neovascularization; regulates the assembly of β1 integrin and fibronectin. MTT assay, wound healing assay, Matrigel tube formation assay. Anti-CD93 nanobodies NC81/NC89 significantly inhibit HUVEC proliferation, migration, and tube formation; they also downregulate VE-cadherin expression. ( 56 ) VCAM-1 (Vascular cell adhesion molecule-1) Expressed on activated endothelium, promoting inflammatory cell recruitment and angiogenesis signal amplification. Atherosclerotic double knockout mice, closed-loop model of human endarterectomy specimens; atherosclerotic mouse models, rabbit atherosclerotic models, human carotid/femoral endarterectomy specimens. Microbubble signaling is enhanced in double knockout mice aortas and human specimens (detectable in early/late plaque inflammation); radiolabeled cAbVCAM-1–5 enables non-invasive imaging and quantification of the degree of atherosclerotic inflammation. ( 38 , 57 , 58 ) MMP-2/MMP-9 (Matrix metalloproteinases) Degrades the basement membrane/ECM to release cryptic growth factors (e.g., VEGF, FGF), promoting EC migration. Recombinant active human MMP-2, human cell lines: HEK293, HeLa, human washed platelets. Inhibits MMP-2 gelatin hydrolysis; dose-dependently inhibits collagen-induced platelet aggregation, P-selectin expression, p38 phosphorylation, thrombin receptor activator peptide 6-enhanced aggregation, and platelet adhesion to MMP-2. ( 59 ) Fibronectin EDB (EDB splice variant) A tumor-specific ECM component that supports neovascular stroma, EC attachment, and the release of pro-angiogenic signals. Triple-negative breast cancer (TNBC) mouse model, pancreatic ductal adenocarcinoma (PDAC) mouse model, melanoma mouse model, breast cancer progression model (MMTV-PyMT mice), pulmonary fibrosis model. 64 Cu-labeled NJB2 highly specifically detects primary tumors and micrometastases; capable of delivering imaging/therapeutic payloads to the ECM of disease sites. ( 60 , 61 ) urokinase-type Plasminogen activator uPA/uPAR Activates plasmin, synergizing with MMPs to degrade the ECM and providing a migration pathway for angiogenesis. In vitro enzyme activity inhibition assay. Specifically binds to uPA; capable of binding to uPA associated with active site inhibitors. ( 62 ) Tenascin-C An ECM glycoprotein that regulates cell adhesion and migration, promoting tumor angiogenesis and stromal remodeling. Ulcerative colitis colon tissue, ora
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