---
title: "Non-Anticoagulant Heparins: Immune Modulation and Therapeutic Advances"
id: "frontiers-in-immunology-18-non-anticoagulant-heparins-glycan-mediated-immune-modulation-and-therapeutic"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-non-anticoagulant-heparins-glycan-mediated-immune-modulation-and-therapeutic"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1855688"
published_at: "2026-07-21T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Non-Anticoagulant Heparins: Immune Modulation and Therapeutic Advances
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-non-anticoagulant-heparins-glycan-mediated-immune-modulation-and-therapeutic
- **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.2026.1855688)
- **Published At:** 2026-07-21T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Non-anticoagulant heparins (NAHs) retain some biological activities of heparin without anticoagulant effects. - NAHs show promise in treating inflammatory disorders, cancer, sepsis, and viral infections by exerting **anti-inflammatory**, **anticancer**, and **antiviral** properties. - They interact with proteins like heparanase and P-selectin, aiding drug delivery through systems like hydrogels and nanoparticles. - The article reviews the preparation methods, biological activities, and mechanisms of NAHs, outlining their therapeutic applications and structure-activity relationships. - Challenges include translational barriers from clinical trials and the need for innovative design to enhance target selectivity and efficacy.
## Clinical Analysis & Structured Key Points
About us All journals All articles Submit manuscript Submit data Search Frontiers in Immunology Sections Articles Research Topics Editorial board About journal Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic The Role of Glycans in Immunotherapy and Immune Modulation: Implications for Autoimmune Diseases, Cancer, and HIV Submission open 5386 views 3 articles Editor & Reviewers Edited by N L Nancy Lola Meulenberg (née: Tumba) Reviewed by P H Prasanna H M V L Vittoria Lopez Outline Abstract 1 Introduction 2 Preparation of non-anticoagulant heparins 3 Biological activities of non-anticoagulant heparins 4 Mechanisms of action of non-anticoagulant heparins 5 Clinical applications of non-anticoagulant heparins 6 Pharmaceutical application of non-anticoagulant heparins 7 Conclusion and future perspectives Author contributions Funding Acknowledgments Conflict of interest Generative AI statement Publisher’s note References 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 Table 1 Structure-activity relationships of heparin derivatives: structural modifications and biological activities. View in article Table 2 Summary of clinical trials. View in article Table 3 Context-dependent effects of NAHs on angiogenesis. View in article Table 4 Translational status of the NAH-based formulation strategies. View in article REVIEW article Front. Immunol., 21 July 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1855688 Non-anticoagulant heparins: glycan-mediated immune modulation and therapeutic applications Y G Yaner Gu 1 Q W Qiong Wang 1 J F Juan Fang 1 J C Jing Chen 1 K H Kaiting Hong 1 Z Z Zhanwei Zhang 1 S S Syed Shams Ul Hassan 2 Y C Yin Chen 2* X Z Xuqian Zhang 1* 1. Zhoushan Maternal and Child Care Hospital, Zhoushan, China 2. School of Food and Medicine, Zhejiang Ocean University, Zhoushan, China Abstract Non-anticoagulant heparins (NAHs) are modified derivatives of heparin that retain many of the biological activities of the parent compound while exhibiting reduced or absent anticoagulant effects. These modifications have unlocked new therapeutic potentials in various diseases, including inflammatory disorders, cancer, sepsis, and viral infections. This review explores the chemical modifications of NAHs, their mechanisms of action, structure-activity relationships, and therapeutic applications. NAHs exert anti-inflammatory, anticancer, antiviral, and vascular protective effects by interacting with key proteins like heparanase, P-selectin, and HMGB1. Furthermore, their application in drug delivery systems, such as hydrogels and nanoparticles, enhances localized therapeutic efficacy. The promising results from preclinical and clinical studies position NAHs as a valuable class of drugs with diverse therapeutic applications, particularly in oncology, infectious diseases, and critical care. 1 Introduction The history of heparin dates back more than a century, when Jay McLean and William Henry Howell first isolated this glycosaminoglycan (GAG) from canine liver in 1916, with subsequent collaborative work leading to its purification and naming as “heparin” (1). Its powerful anticoagulant activity quickly established the compound as an essential therapeutic agent for thromboprophylaxis and embolism prevention. Structurally, heparin is a linear, highly sulfated polysaccharide composed of repeating disaccharide units of uronic acid (either iduronic acid or glucuronic acid) and glucosamine. These units are variably sulfated at multiple positions (N-, 2-O-, and 6-O-sulfation), giving the molecule dense negative charges and strong affinity for various proteins (Figure 1) (2). Figure 1 Structure of heparin. The repeating disaccharide unit consists of uronic acid (either L-iduronic acid, IdoA, or D-glucuronic acid, GlcA) and D-glucosamine (GlcN), linked by α (1→4) glycosidic bonds. Sulfation occurs at multiple positions: N-sulfation (N-S) on glucosamine, and O-sulfation at the 2-O-position of uronic acid and the 6-O-position of glucosamine. The unique pentasaccharide sequence (shown in the dashed box) constitutes the antithrombin III (AT-III) binding site, which is critical for the anticoagulant activity of unfractionated heparin. NAHs are generated by chemical modifications that disrupt this pentasaccharide motif while preserving other biological activities. This image is created by the authors using KingDraw. The anticoagulant properties of heparin depend largely on its ability to bind antithrombin III (AT-III), a key regulator of the coagulation cascade. Within the heparin polymer, a unique pentasaccharide motif engages AT-III and triggers a conformational rearrangement that markedly potentiates the inhibitor’s activity against thrombin (factor IIa) and factor Xa (Figure 1), two critical enzymes in the coagulation cascade (3). This interaction accelerated the neutralization of these coagulation factors by up to 1,000-fold, effectively preventing fibrin clot formation (4). Despite its widespread use, particularly in high-risk surgical and medical settings, the therapeutic applications of heparin extended far beyond its anticoagulant properties. Recent studies have uncovered its non-anticoagulant effects, such as anti-inflammatory, anticancer, antiviral, and vascular protective properties, which have significantly expanded its clinical utility (5–12). This review systematically examines the preparation, biological activities, and mechanisms of action of NAHs, with particular emphasis on quantitative structure-activity relationships that link specific chemical modifications to selective target recognition. Previous reviews have explored the therapeutic potential of NAHs from distinct angles: Cao et al. (13) focused on their application in COVID-19; Lanzi et al. (14) discussed their role in sarcoma; Sultana et al. (15) and Wang et al. (16) provided overviews of antiviral and anticoagulant applications; and Zeng et al. (17) summarized general anti-inflammatory and anticancer mechanisms. While these contributions have advanced the field, they largely treat these therapeutic areas—anti-inflammatory, anticancer, vascular protective, and antiviral effects—as separate topics, each considered in isolation. In contrast, this review provides an integrated framework that bridges chemical structure-activity relationships (SAR) with molecular mechanisms of immune modulation, presenting these diverse therapeutic activities as a cohesive network of glycan-mediated protein interactions involving shared targets such as heparanase, P-selectin, and HMGB1. Furthermore, we critically assess the translational barriers highlighted by recent clinical failures (RASTEN, FRAGMATIC, necuparanib, PI-88) and discuss how target-selective NAH design and delivery innovations may overcome these obstacles. By unifying chemical, mechanistic, and clinical perspectives, this review aims to provide a practical roadmap for developing NAH-based therapies with improved target selectivity and reduced bleeding risk. 2 Preparation of non-anticoagulant heparins 2.1 Chemical modification techniques The preparation of NAHs involved specific chemical modifications designed to remove the anticoagulant activity of heparin while retaining its other therapeutic benefits. Key strategies include periodate oxidation, N-desulfation, and glycol-splitting (Figure 2) (18, 19). Figure 2 Preparation of non-anticoagulant heparins. Three chemical strategies are shown: (1) Periodate oxidation cleaves the C2-C3 bond of unsulfated uronic acids, generating flexible glycol-split (gs) residues and disrupting the AT-III binding site. (2) N-desulfation removes N-sulfate groups from glucosamine, which may be followed by N-acetylation. (3) Glycol-splitting (periodate oxidation followed by reduction) converts non-sulfated uronic acids to gs residues. This image is created by the authors using KingDraw. 2.1.1 Periodate oxidation Among the various chemical modification strategies, periodate oxidation remains a widely employed approach for generating NAHs. This technique selectively targets vicinal diol groups located on unsulfated glucuronic acid (GlcA) residues within the pentasaccharide domain responsible for AT-III binding. Cleavage of these diol moieties effectively abolishes the conformational integrity required for AT-III recognition, thereby eliminating anticoagulant activity (20). This modification eliminated the anticoagulant activity while preserving the molecule’s ability to interact with other important biological targets, such as heparanase and P-selectin, which are involved in inflammation and cancer progression (21). 2.1.2 N-desulfation Another method, N-desulfation, led to the removal of sulfate groups from the glucosamine residues in heparin (22). For example, the use of enzymes such as N-sulfatases that specifically targeted the sulfate groups attached to the nitrogen of the glucosamine residues (23, 24). These enzymes cleaved the sulfate groups without affecting the backbone of the heparin molecule. Since sulfate groups were essential for activating antithrombin III, their removal significantly reduced heparin’s anticoagulant effects, allowing it to retain its biological activities related to immune modulation, cancer metastasis, and inflammation (25). 2.1.3 Glycol-splitting Glycol-splitting was a chemical modification that treating heparin with sodium periodate to selectively cleave the C2-C3 vicinal diol moiety in the unsulfated glucuronic acid (GlcA) and iduronic acid (IdoA) residues of the polysaccharide. This treatment resulted in the formation of a ring-opened dialdehyde residue, which was subsequently reduced with sodium borohydride. Following reduction, the product was cleaved with acid to yield NAHs with a reduced molecular weight (26). Nitrous acid depolymerization of the porcine intestinal heparin was another method to prepare NAHs (27). Nitrous acid specifically cleaved the glycosidic bonds between glucosamine (GlcN) and uronic acid. The reaction involved the formation of an N-nitroso derivative at the amine group of the glucosamine (28). The resulting fragments retained an intact AT-III binding site and possess clinically significant anti-Xa activity (typically 70–120 IU/mg). Therefore, nitrous acid depolymerization as low molecular weight heparins (LMWHs) alone does not produce true NAHs. To convert LMWHs into NAHs, additional chemical modifications—such as periodate oxidation and glycol-splitting—are required to disrupt the AT-III binding site. These smaller fragments had disrupted AT-III binding site and exhibited reduced anticoagulant activity but retained other therapeutic properties, such as anti-inflammatory and anticancer effects. The reduced molecular size improved their bioavailability and tissue penetration, making them suitable for localized treatment of diseases like cancer and inflammatory conditions (29). 2.2 Structural characterization of non-anticoagulant heparins Although both heparin and its derivatives could bind to various heparin-binding proteins, such as P-selectin and heparanase, the key distinction lied in their anticoagulant activity. Unfractionated Heparin (UFH) is a highly charged, large molecule that strongly activated AT-III, leading to its anticoagulant effects. In contrast, NAHs are engineered to avoid this interaction, making them particularly useful in therapeutic areas focused on inflammation, cancer progression, and immune modulation, while minimizing the risk of bleeding (30, 31). Advanced characterization techniques, including high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy, were used to confirm structural changes and to verify that the desired modifications are achieved without compromising therapeutic properties. NMR spectra could provide information on the persistence of key functional groups, such as the sulfation pattern of the heparin backbone can be confirmed by analyzing the distinct chemical shifts corresponding to different sulfate positions on the sugar residues (32). Additionally, HPLC-MS assay had been developed to analyze the 3-O-sulfo group-containing tetrasaccharides, allowing for precise measurement of the AT-III-binding site variants (33). In detail, heparin was often treated with heparin lyase II, an enzyme that cleaves the heparin polysaccharide chains into tetrasaccharide fragments (34). These fragments were resistant to further enzymatic digestion and contain the essential 3-O-sulfo groups involved in the antithrombin-binding interaction. This approach provided insights into the natural variability of the antithrombin-binding region across different heparin sources and was crucial for distinguishing NAHs from normal heparin (35). This source-dependent structural variability extends beyond the AT-III-binding site to the entire heparin chain. Pharmaceutical heparin is primarily derived from porcine intestinal mucosa, but bovine lung and bovine intestinal heparins are also commercially available. These sources differ in molecular weight distribution, sulfation pattern, and anticoagulant activity (36, 37). Porcine heparin contains a higher proportion of the antithrombin-binding pentasaccharide and exhibits higher specific activity than bovine heparins. For NAH preparation, source heterogeneity introduces additional batch-to-batch variability that must be considered during manufacturing and quality control. 3 Biological activities of non-anticoagulant heparins 3.1 Anti-inflammatory properties One of the most significant therapeutic properties of NAHs was their ability to modulate inflammation. Cell-based and animal studies have demonstrated that these derivatives acted by inhibiting leukocyte adhesion to endothelial cells, a key event in the inflammatory response. By binding to P-selectin and inhibiting heparanase activity, NAHs prevented the interaction between leukocytes and endothelial cells, reducing immune cell infiltration at sites of inflammation (38, 39). Additionally, NAHs suppressed the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibit the activation of HMGB1 (Figure 3), thereby mitigating inflammatory responses in conditions such as sepsis and autoimmune diseases (41, 42). Figure 3 Schematic illustration of anti-inflammatory activity of NAHs. The anti-inflammatory effects include three general mechanisms: NAHs inhibit (1) pro-inflammatory cell infiltration by suppressing neutrophil and leukocyte recruitment and adhesion; (2) IL-6 function through NF-κB inhibition and direct IL-6 binding; and (3) HMGB1 activation. The schematic was designed based on the mechanistic framework described in the literature (40). This image is created by the authors using SciDraw. Beyond these well-characterized pathways, emerging evidence suggests that NAHs may also modulate broader inflammatory networks. Heparin and its derivatives have been shown to interfere with complement activation, particularly through binding to complement components such as C1q and C3, thereby attenuating complement-mediated tissue injury (43). Additionally, NAHs can bind to a range of chemokines including CXCL8 (IL-8) and CCL2 (MCP-1), disrupting their chemotactic gradients and reducing the recruitment of neutrophils and monocytes to inflammatory sites (44). This interference with chemokine–glycosaminoglycan interactions represent an additional layer of anti-inflammatory activity that complements the direct inhibition of cytokine release and leukocyte adhesion. Furthermore, heparin has been shown to modulate the NF-κB signaling pathway in endothelial cells and monocytes, reducing the transcription of multiple pro-inflammatory genes (45). These pleiotropic effects on the complement, chemokine, and transcription factor networks further underscore the therapeutic potential of NAHs in inflammatory diseases, particularly in conditions where multiple inflammatory mediators converge, such as sepsis, acute respiratory distress syndrome, and chronic autoimmune disorders. 3.2 Anticancer effects NAHs exhibited potent anticancer effects by targeting multiple pathways involved in tumor progression. They inhibited tumor metastasis by preventing heparanase, an enzyme that cleaved heparan sulfate chains within the extracellular matrix (ECM), which was essential for cancer cells to invade and spread. By inhibiting heparanase activity, NAHs reduced tumor cell migration and invasion (46, 47). In addition, NAHs had been shown to suppress angiogenesis, the process by which tumors form new blood vessels to supply nutrients and oxygen. By blocking key signaling molecules like vascular endothelial growth factor (VEGF) and Basic Fibroblast Growth Factor (bFGF), NAHs prevented the formation of new blood vessels, effectively starving the tumor and limiting its growth (17, 48). Beyond its direct effects on tumor cells and angiogenesis, the tumor microenvironment contains various immune cell populations that influence cancer progression. Among these, tumor-associated macrophages (TAMs) are particularly abundant and typically exhibit an M2-like immunosuppressive phenotype that promotes tumor growth and immune evasion. Recent evidence suggests that NAHs can modulate this polarization state. Using a murine macrophage cell line, Zhu et al. (49) demonstrated that N-desulfated and reacetylated heparin derivatives promote a shift from M2-like to M1-like polarization. This effect was mediated by the STAT6 pathway and was associated with reduced M2 markers (Arg-1, CD206) and increased pro-inflammatory cytokines (IL-12, TNF-α). These findings suggest that certain NAH modifications may help reprogram the immunosuppressive tumor microenvironment, although direct evidence in tumor-bearing hosts remains to be established. In addition, heparin and its derivatives can neutralize damage-associated molecular patterns (DAMPs) such as extracellular histones, which are released from necrotic and apoptotic cells within the tumor microenvironment and promote inflammation, endothelial injury, and thrombosis (50). Heparin binds to positively charged histones through electrostatic interactions, an effect that is independent of its anticoagulant activity and is retained by non-anticoagulant derivatives (38). By mitigating DAMP-mediated inflammation, NAHs may indirectly suppress tumor progression, though this mechanism is primarily anti-inflammatory rather than directly immunomodulatory.Early studies demonstrated that the glycol-split heparin derivative had shown promise in cancer models, significantly reducing tumor growth and metastasis in preclinical studies. These preclinical findings suggest that NAHs may have potential value as part of combination therapies for cancer treatment. However, several caveats should be noted. First, most of these studies were conducted in murine xenograft models, which may not fully recapitulate human tumor biology or the tumor microenvironment. Second, the effective doses used in animal studies (typically 10–20 mg/kg daily) are often substantially higher than those achievable in patients without bleeding risk, particularly for anticoagulant LMWHs. Third, as discussed, clinical translation of these promising preclinical results has been challenging, with several Phase III trials failing to demonstrate survival benefit. Therefore, while NAHs hold promise, rigorous clinical evaluation is required to establish their therapeutic efficacy in cancer patients (Figure 4) (51). Figure 4 Schematic illustration of anti-tumor activity of NAHs. NAHs inhibit (1) heparanase-mediated ECM degradation, (2) VEGF/FGF-driven angiogenesis, and (3) tumor-associated inflamm
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