Smart Thrombosis Care: The Rise of Closed-Loop Diagnosis-to-Treatment Nano Systems

Jiong Wu; Yuanyuan Zhang; Wu Chen; Tianjiao Hao; Chuanjiang Ran; Yuanyuan Zhou; Yan Shen; Wei You; Tao Wang

doi:10.2147/IJN.S530884

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Review

Smart Thrombosis Care: The Rise of Closed-Loop Diagnosis-to-Treatment Nano Systems

Authors Wu J, Zhang Y, Chen W, Hao T, Ran C, Zhou Y, Shen Y, You W, Wang T

Received 27 March 2025

Accepted for publication 10 June 2025

Published 19 June 2025 Volume 2025:20 Pages 7851—7868

DOI https://doi.org/10.2147/IJN.S530884

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. RDK Misra

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Jiong Wu,^1,^* Yuanyuan Zhang,^2,^* Wu Chen,^1,^* Tianjiao Hao,¹ Chuanjiang Ran,¹ Yuanyuan Zhou,¹ Yan Shen,¹ Wei You,³ Tao Wang⁴

¹Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People’s Republic of China; ²Department of Pharmacy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, People’s Republic of China; ³Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; ⁴Department of Clinical Laboratory, Second People’s Hospital of Taixing City, Taixing, Jiangsu Province, 225400, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Wei You, Email [email protected] Tao Wang, Email [email protected]

Abstract: Thrombosis continues to be a leading cause of morbidity and mortality worldwide, presenting complex pathophysiological challenges that complicate effective diagnosis and treatment. A holistic approach to thrombosis management, incorporating integrated diagnostic and therapeutic systems, is essential for improving patient outcomes. This review explores the emerging concept of closed-loop diagnosis-to-treatment nanosystems in thrombosis care, with a focus on integrating advanced technologies. Specifically, we examine the targeting of critical components involved in thrombosis, including platelets, coagulation factors, endothelial cells, the fibrinolytic system, and the immune system. Techniques such as platelet aggregation assays, coagulation function tests, biomarker detection, and nanotechnology-based therapies are discussed. Moreover, the application of these integrated systems is reviewed in both the acute and chronic phases of thrombosis, covering conditions such as acute coronary syndrome, acute pulmonary embolism, chronic deep vein thrombosis, and post-surgical thrombosis prevention. Finally, the review highlights potential future developments in integrated thrombosis care, with an emphasis on personalized treatment strategies and the role of emerging technologies in enhancing clinical outcomes. These insights underscore the transformative potential of closed-loop nano-systems in achieving more precise, timely, and effective thrombosis management.

Keywords: thrombosis, nanotechnology, integrated management

Graphical Abstract:

Introduction

Thrombosis-related diseases, including deep vein thrombosis (DVT), pulmonary embolism (PE), and coronary artery thrombosis, impose a substantial global health burden. These conditions contribute to high morbidity and mortality rates, with venous thromboembolism (VTE) alone affecting millions of individuals annually.¹ In the United States and Europe, VTE accounts for an estimated 300,000 to 600,000 deaths per year, often due to complications such as PE. The economic burden is equally significant, as healthcare systems allocate substantial resources to hospitalization, long-term anticoagulation therapy, and the management of recurrent thrombotic events.² Development of diagnosis and treatment of thrombosis is shown in Figure 1. Despite advancements in thrombosis management, major challenges persist in early diagnosis, risk stratification, and individualized treatment, underscoring the urgent need for more effective and integrated approaches.³

Figure 1 Development of diagnosis and treatment of thrombosis.

One of the primary challenges in thrombosis management is the difficulty of early diagnosis. The process of thrombus formation is illustrated in Figure 2. Thrombotic events often develop asymptomatically or present with nonspecific clinical manifestations, leading to frequent misdiagnoses or delayed interventions.⁴ Current diagnostic methods, such as D-dimer testing and imaging modalities like computed tomography (CT) and ultrasound, have inherent limitations. While D-dimer testing exhibits high sensitivity, its low specificity frequently results in false-positive findings, necessitating additional confirmatory imaging. However, imaging techniques require specialized equipment and trained personnel, limiting their availability and timely application, particularly in resource-constrained settings.⁵ The lack of real-time monitoring further complicates disease management, as thrombosis progresses dynamically and necessitates continuous assessment rather than single-point diagnostics.

Figure 2 The process of thrombosis.

Treatment strategies for thrombosis are also hindered by uncertainties in therapeutic decision-making.⁶ Anticoagulants, antiplatelet agents, and thrombolytic therapies serve as the cornerstone of pharmacological interventions, yet their clinical application must be highly individualized. Patient-specific factors, including genetic predispositions, comorbidities, and drug metabolism variability, significantly influence treatment efficacy and safety. Improper dosing or inadequate therapy can lead to severe complications, such as hemorrhagic events or recurrent thrombosis.⁷ The lack of precise, real-time guidance often results in suboptimal treatment outcomes, highlighting the necessity for personalized, adaptive therapeutic strategies that integrate diagnostic and therapeutic processes into a seamless, closed-loop system.

A closed-loop thrombosis management system is essential to overcoming the limitations of conventional approaches.⁸ Traditional thrombosis care relies on static assessments and empirical treatment decisions, which fail to capture the dynamic nature of thrombus formation and resolution. Furthermore, the fragmented nature of current diagnostic and therapeutic workflows leads to delays in clinical decision-making and potential treatment inefficacies.⁹ A smart thrombosis care system, integrating real-time monitoring, data-driven decision-making, and automated therapeutic adjustments, has the potential to revolutionize disease management. Leveraging multimodal biosensing technologies, such a system can continuously monitor key thrombosis-related parameters, including platelet activation, coagulation cascade dynamics, endothelial function, fibrinolysis, and immune responses.¹⁰ The incorporation of artificial intelligence (AI) and big data analytics enables precise risk stratification and individualized therapeutic modulation, optimizing treatment while minimizing adverse effects.¹¹ Additionally, smart drug delivery systems can facilitate targeted, controlled-release therapies, ensuring that anticoagulation and thrombolysis are finely tuned to the patient’s physiological state.

The realization of a closed-loop thrombosis care system necessitates advancements across multiple technological domains. Multimodal biosensors play a crucial role in capturing real-time biological signals associated with thrombosis, allowing for continuous assessment of hemostatic balance.¹² Nanotechnology and smart drug delivery platforms hold the potential to enable precision therapeutics by delivering anticoagulants, antiplatelet agents, or thrombolytics in response to physiological cues. AI-driven decision support systems, leveraging predictive analytics and machine learning algorithms, facilitate dynamic treatment adjustments based on evolving patient data.¹³ The integration of these components into a cohesive framework paves the way for next-generation thrombosis management, bridging the gap between diagnosis and treatment through automation and intelligence.

This review will examine the technological landscape of integrated thrombosis management, beginning with an in-depth discussion of key targets in thrombosis care, including platelets, coagulation factors, endothelial function, the fibrinolytic system, and immune responses. Subsequently, we will explore the application of these integrated technologies in both acute and chronic thrombosis management, emphasizing their potential to improve clinical outcomes. Finally, we will discuss future perspectives, addressing challenges and opportunities in the development and implementation of smart thrombosis care systems. Through this comprehensive analysis, we aim to elucidate the transformative potential of closed-loop diagnosis-to-treatment systems in modern thrombosis management.

Nanotechnology Enables Precision Targeting for Thrombosis

Given the clinical urgency and challenges of thrombosis, integrated nano-based management platforms are essential for improving patient outcomes. Conventional diagnostics and therapies often operate separately, causing delays and reducing efficacy. In contrast, nano-enabled theranostic systems integrate real-time thrombus detection with targeted therapy, enhancing precision and efficiency.¹⁴ Nanoparticles improve thrombus imaging through MRI, PAI, and fluorescence, while nanocarriers enable controlled, site-specific drug delivery, minimizing systemic side effects. This section explores recent advances in nano-based thrombosis management, focusing on six key targeting strategies: endothelial injury, platelets, coagulation factors, red blood cell–thrombus interactions, fibrin, and inflammation (Table 1). These nanoscale strategies enable more accurate diagnosis, personalized treatment, and real-time thrombus monitoring, advancing patient-centered care.

Table 1 The Six Targets of the Integrated Thrombosis Diagnosis and Treatment Technology

Endothelial Injury Targeting

Endothelial injury plays a pivotal role in thrombus formation by initiating platelet adhesion, leukocyte recruitment, and activation of the coagulation cascade.²¹ Dysfunctional endothelial cells upregulate adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), facilitating interactions with circulating immune cells and platelets and thereby accelerating thrombus development. Furthermore, endothelial dysfunction reduces the bioavailability of nitric oxide (NO) and prostacyclin, exacerbating vascular inflammation and fostering a pro-thrombotic state.^22–24 Given its central role in thrombogenesis, targeting endothelial dysfunction represents a promising strategy for integrated thrombus diagnosis and therapy.^25–28

Current theranostic approaches for endothelial injury encompass both imaging and therapeutic interventions.²⁹ Molecular imaging techniques utilize fluorescent probes targeting endothelial adhesion molecules, such as VCAM-1 and ICAM-1, enabling noninvasive visualization of endothelial activation and early thrombus formation.³⁰ Concurrently, NO-releasing nanocarriers have emerged as multifunctional platforms capable of restoring endothelial function while serving as contrast agents for imaging.³¹ NO possesses vasodilatory, anti-inflammatory, and antithrombotic properties, making it an attractive therapeutic agent for vascular protection.³² By incorporating NO donors into nanocarriers, these systems achieve controlled NO release at sites of endothelial dysfunction, mitigating oxidative stress, inhibiting platelet aggregation, and enhancing imaging contrast.³³ Shi et al developed NO-loaded lipid microbubbles (NO-MBs) combined with ultrasound-targeted microbubble destruction (UTMD) for precise thrombolysis.³⁴ This strategy enables targeted NO release under real-time ultrasound imaging, enhancing thrombus dissolution while minimizing systemic effects, as shown in Figure 3A. Notably, cavitation stimulated endothelial cells to produce endogenous NO, further promoting thrombolysis and vascular repair. NO-MBs also alleviated oxidative stress and inflammation, demonstrating excellent biosafety. These findings highlight the endothelial-targeted potential of NO-MBs for arterial thrombosis treatment.

Figure 3 Schematic Representations of Advanced Nano-Platforms for Thrombosis Diagnosis and Therapy. (A) Diagram of the structure, synthesis, and mechanism of action of NO-MBs. Reprinted from Europ J Pharm Biopharm. Volume 205. Shi B, Yang Q, Liang Z, et al. Accelerating thrombolysis of arterial thrombus with NO-MBs UTMD therapy. 114566. Copyright 2024, with permission from Elsevier. Creative Commons.³⁴ (B) Schematic illustration of PNP-PA design and its characterization. The red arrow indicates that the platelet membrane has successfully transferred to the desired coating direction. Reprinted from Xu J, Zhang Y, Xu J, et al. Engineered nanoplatelets for targeted delivery of plasminogen activators to reverse thrombus in multiple mouse thrombosis models. Adv Mate. 2020;32(4):1905145. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.³⁵ (C) Role of TO_SP-3 in the diagnosis and treatment of thrombosis. Reprinted from Inter J Biolog Macromolecules. Volume: 306. George AM, Chakraborty K, Paulose SK, Jalal S, Pai AA, Dhara S. Anticoagulant potential of sulfated galactofucan from Turbinaria ornata: targeting coagulation pathways and thrombin signaling in human umbilical vein endothelial cells. 141499. Copyright 2025, with permission from Elsevier.³⁶ (D)Therapeutic Mechanisms of USIO/UK@EM for Thrombosis Removal. Reprinted from Zhu L, Lian W, Yu N, et al. Erythrocyte-membrane-camouflaged magnetic nanocapsules with photothermal/magnetothermal effects for thrombolysis. Adv Healthc Mater. 2024;13(20):e2400127. © 2024 Wiley-VCH GmbH.³⁷ (E)Schematic illustration of an ultrasound-responsive theranostic platform. Reprinted from Lin L, Ba Z, Tian H, et al. Ultrasound-responsive theranostic platform for the timely monitoring and efficient thrombolysis in thrombi of tPA resistance. Nat Commun. 2024;15(1):6610. Creative Commons.³⁸

Note: *p<0.05

Despite these advancements, several challenges remain in optimizing endothelial-targeted theranostic platforms.³⁹ A key limitation is the need for enhanced targeting specificity to minimize off-target effects and improve diagnostic precision. Functionalizing nanocarriers with endothelial-specific ligands, such as peptides or antibodies against VCAM-1 or ICAM-1, could enhance selective accumulation at sites of endothelial injury.⁴⁰ Additionally, extending systemic circulation time through polyethylene glycol (PEG) modification or biomimetic coatings could improve in vivo stability and prolong therapeutic effects. Another promising strategy is the development of stimuli-responsive nanocarriers that release NO in response to pathological cues, such as oxidative stress or shear stress alterations in thrombogenic regions. Refining these approaches could lead to more precise, efficient, and clinically translatable endothelial-targeted theranostic platforms for thrombus management.

Platelet Targeting

Platelets play a central role in primary thrombus formation by adhering to the injured vascular endothelium, undergoing activation, and facilitating the deposition of coagulation factors.⁴¹ Upon activation, platelets release procoagulant molecules and express surface receptors that promote aggregation, leading to the formation of a platelet-rich thrombus core.^42–45 This process forms a scaffold for stabilizing the fibrin network, highlighting platelets as a key target for thrombus theranostics.⁴⁶ Strategies aimed at detecting and modulating platelet activity hold significant potential for enabling early diagnosis and intervention, thereby reducing the risk of thrombotic complications.

Current platelet-targeted theranostic technologies integrate molecular imaging with therapeutic functionalities to achieve precise thrombus detection and treatment.⁴⁷ Platelet membrane-coated biomimetic nanoparticles represent an advanced strategy for targeting thrombi, as they retain the natural adhesion properties of platelets, allowing for selective accumulation at thrombotic sites.⁴⁸ These biomimetic nanocarriers can be engineered to carry contrast agents for imaging and thrombolytic agents for therapy, enabling dual functionality.⁴⁹ Xu et al developed platelet membrane-coated polymer nanoparticles for targeted delivery of recombinant tissue plasminogen activator (rt-PA) to the thrombus site for thrombolytic therapy.³⁵ In vitro targeting and thrombolytic efficacy of PNP-PA are shown in Figure 3B. Additionally, fluorescence-based platelet aggregation probes have been developed to detect activated platelets in real-time. These probes selectively bind to surface markers expressed on activated platelets, providing a noninvasive approach to visualize thrombus formation and assess platelet function in vivo.

Despite these advancements, challenges persist in enhancing the resolution and specificity of platelet-targeted imaging and therapy.⁵⁰ A key limitation is the need for improved imaging sensitivity to distinguish thrombotic lesions from surrounding vascular structures with high precision.^51,52 Future strategies may focus on the development of multimodal imaging probes that integrate fluorescence, magnetic resonance, and photoacoustic imaging to improve diagnostic accuracy. Additionally, optimizing the stability and biocompatibility of platelet-mimicking nanocarriers could extend their circulation time and enhance therapeutic efficacy.⁵³ Addressing these limitations could facilitate the development of next-generation platelet-targeted theranostic platforms, offering more effective and personalized approaches for thrombus diagnosis and treatment.

Coagulation Factor Targeting

The coagulation cascade is a tightly regulated process in which coagulation factors, particularly thrombin and factor Xa (FXa), play a pivotal role in amplifying clot formation.⁵⁴ Thrombin, a key serine protease, catalyzes the conversion of fibrinogen to fibrin and further activates platelets, thereby enhancing thrombus stability.^55–58 FXa, positioned at the convergence of the intrinsic and extrinsic coagulation pathways, acts as a central mediator of thrombin generation, making it a key target for anticoagulant strategies.⁵⁹ Given the cascading nature of coagulation factor activation, precise modulation is critical to prevent excessive thrombosis while minimizing the risk of bleeding.⁶⁰ George et al identified TO_SP-3, a sulfated polysaccharide from Turbinaria ornata, as a potent anticoagulant that targets coagulation factors.³⁶ TO_SP-3 significantly prolonged clotting times and suppressed factor Xa expression by 89% in endothelial cells, demonstrating its regulatory effects on both intrinsic and extrinsic pathways, as shown in Figure 3C. It effectively inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation while reducing thrombin production by 33%. Through electrostatic interactions, TO_SP-3 modulated the coagulation cascade more efficiently than heparin, highlighting its potential as a natural anticoagulant for thrombotic disorder management.⁶¹

Current theranostic approaches targeting coagulation factors integrate imaging with anticoagulant therapy, enabling real-time thrombus monitoring and controlled drug release.^62,63 Thrombin-responsive nanocarriers have been developed to achieve adaptive anticoagulation, wherein thrombin-mediated cleavage triggers the localized release of anticoagulant agents in a self-regulated manner.⁶⁴ Similarly, FXa inhibitor-loaded nanoparticles have been designed to prolong drug circulation, enhance therapeutic efficacy, and reduce systemic bleeding risks.⁶⁵ These nanosystems employ targeted delivery strategies to localize anticoagulant effects at thrombotic sites, thereby improving safety and efficacy compared to conventional anticoagulant therapies.

Despite these advancements, challenges remain in optimizing coagulation factor-targeted theranostics.⁶⁶ A primary concern is the risk of excessive anticoagulation, which may lead to hemorrhagic complications. Future research should focus on developing highly selective and dynamically responsive drug delivery systems that adapt to pathological coagulation factor levels while preserving hemostatic balance.⁶⁷ Additionally, improving the biocompatibility of anticoagulant nanocarriers and hydrogels is crucial to minimizing immune responses and enhancing long-term safety.⁶⁸ Strategies such as surface modification with biomimetic coatings or the incorporation of responsive polymeric architectures could further refine these platforms. Addressing these limitations will be critical for advancing next-generation coagulation factor-targeted theranostic technologies, ultimately enabling safer and more effective thrombus diagnosis and treatment.

Red Blood Cell–Thrombus Interaction Targeting

Red blood cells (RBCs) play a critical role in thrombus stability by influencing clot architecture and modulating fibrinolysis.⁶ Within the thrombus microenvironment, RBCs become enmeshed in the fibrin network, increasing thrombus density and mechanical resistance to degradation. Additionally, RBC-derived microparticles contribute to procoagulant activity by exposing phosphatidylserine, which serves as a catalytic surface for coagulation factor assembly.^69–72 These interactions not only enhance thrombus stability but also affect the efficacy of thrombolytic therapies, making RBC-thrombus interactions a promising target for theranostic strategies to enhance thrombus detection and facilitate efficient clot dissolution.

Emerging theranostic technologies targeting RBC-thrombus interactions integrate both imaging and therapeutic functions, enabling real-time thrombus visualization and controlled thrombolysis.⁷³ RBC membrane-coated nanoparticles have been developed to exploit the prolonged circulation time of native RBCs, thereby enhancing thrombus imaging and drug delivery.⁷⁴ These biomimetic carriers improve thrombus-targeting efficiency while reducing immune clearance, ultimately enhancing diagnostic accuracy and therapeutic efficacy.⁷⁵ Furthermore, hemoglobin-based nanocomposites have been engineered for photoacoustic imaging and thrombolysis, leveraging hemoglobin’s strong optical absorption properties to enhance imaging contrast while simultaneously mediating oxygen delivery to accelerate fibrinolysis.⁷⁶ Zhu et al developed erythrocyte membrane (EM)-camouflaged nanocapsules (USIO/UK@EM) for targeted thrombolysis, integrating ultra-small iron oxide (USIO) and urokinase (UK).³⁷ Therapeutic Mechanisms of USIO/UK@EM for Thrombosis Removal are shown in Figure 3D. The EM coating enhanced circulation time (t₁/₂ = 3.28h), enabling prolonged thrombus targeting. Leveraging photothermal and magnetothermal effects, USIO/UK@EM rapidly increased local temperature under laser or magnetic stimulation, significantly improving thrombolytic efficiency (82.4% vs ~15% for UK alone). In vivo studies demonstrated effective dissolution of venous and arterial thrombi in mice and rabbits. This biomimetic platform presents a promising erythrocyte-targeted nanomedicine approach for thrombolytic therapy.

Despite these advancements, several challenges remain in optimizing RBC-targeted theranostics for thrombus management.⁷⁷ Enhancing the specificity of these platforms for large thrombi and deeply embedded clots remains a critical focus, as current targeting strategies may be limited by the heterogeneous composition of thrombi.^78,79 Additionally, optimizing photothermal thrombolysis efficiency requires improved light penetration and controlled energy deposition to prevent collateral tissue damage.⁸⁰ Future research should prioritize the development of multifunctional nanocomposites that combine RBC-mimetic properties with enhanced photothermal conversion efficiency or stimulus-responsive drug release mechanisms.⁸¹ Addressing these challenges will be essential for advancing RBC-targeted theranostic technologies and improving precision thrombus imaging and therapy.

Fibrin Targeting

Fibrin plays a central role in the structural integrity of mature thrombi, serving as the primary scaffold that stabilizes clot formation and resists degradation.⁸² As the final product of the coagulation cascade, fibrin polymerizes into a dense network that entraps platelets and red blood cells, reinforcing thrombus stability and hindering fibrinolysis.^83–86 Given its critical role in thrombus persistence, fibrin represents a key therapeutic target for thrombolysis, particularly in pathological conditions where excessive clot formation leads to vascular occlusion and ischemic complications.⁸⁷ Strategies that selectively target fibrin enable precise thrombus imaging and efficient clot dissolution while minimizing off-target effects.

Current theranostic technologies designed for fibrin targeting integrate advanced imaging modalities with fibrinolytic therapy, enabling real-time thrombus visualization and controlled degradation.⁸⁸ Fibrin-specific fluorescent probes have been developed for MRI and CT imaging, providing high-contrast thrombus detection through selective fibrin binding.⁸⁹ These imaging agents enhance diagnostic accuracy and allow clinicians to monitor thrombus progression and therapeutic response. Additionally, fibrin-targeted nanoscale thrombolytics have been engineered to improve clot dissolution efficiency. These nanocarriers encapsulate fibrinolytic agents such as tissue plasminogen activator (tPA) and are designed to release their therapeutic payload in response to external stimuli, such as ultrasound. By incorporating targeted delivery mechanisms, these nanosystems enhance thrombolytic efficacy while reducing systemic bleeding risks associated with conventional fibrinolytic therapy. Lin et al developed a noninvasive theranostic platform integrating sonodynamic and mechanical thrombolysis for treating tPA-resistant thrombi under ultrasonic imaging guidance.³⁸ Analysis of patient-derived thrombi revealed that fibrin scaffolds, neutrophil extracellular traps (NETs), and ε-(γ-glutamyl) lysine isopeptide bonds form a structural network conferring resistance to tPA, as shown in Figure 3E. Targeting this fibrin-based framework, the proposed strategy achieved over 90% recanalization in a rat model, with sustained vascular reconstruction and no thrombosis recurrence. Successful application in pigs and thrombosis-prone tissue-engineered vascular grafts underscores its translational potential for fibrin-targeted thrombolysis in clinical settings.

Despite these advancements, several challenges remain in optimizing fibrin-targeted theranostic strategies.⁹⁰ Enhancing the thrombolytic efficiency of these systems requires improvements in fibrin affinity and drug release kinetics to ensure rapid and complete clot dissolution.⁹¹ Additionally, minimizing off-target fibrinolysis is essential to reduce hemorrhagic risk. Future research should focus on developing multifunctional nanocarriers that integrate fibrin targeting with stimuli-responsive drug release while exploring alternative thrombus imaging techniques with higher resolution and real-time monitoring capabilities.^92,93 Addressing these challenges will be crucial for advancing fibrin-targeted theranostic platforms and improving personalized thrombolytic therapy.

Inflammation and Immune Targeting

Inflammation and immune responses play a critical role in thrombus stabilization and post-thrombotic complications, with neutrophil extracellular traps (NETs) serving as key contributors to thrombus persistence.^94–97 NETs, composed of DNA, histones, and granular proteins, form a fibrous network that reinforces thrombus structure, promotes platelet aggregation, and exacerbates vascular occlusion.^98,99 Moreover, NETs impede fibrinolysis and contribute to endothelial dysfunction, thereby hindering vessel recanalization and increasing the risk of thrombosis recurrence.^100,101 Given their pivotal role in thrombus pathophysiology, targeting NETs and modulating the inflammatory microenvironment represent promising strategies for integrated thrombus diagnosis and therapy.¹⁰²

Current theranostic approaches focus on NET-targeted nano-delivery systems that integrate anti-inflammatory and thrombolytic functions.^103,104 These nanoparticles are designed to selectively bind NET components, facilitating precise drug delivery while simultaneously serving as imaging agents for thrombus detection.¹⁰⁵ By incorporating thrombolytic agents such as DNase I or anti-NET antibodies, these nanosystems promote NET degradation, enhance clot resolution, and attenuate the inflammatory response.¹⁰⁶ Additionally, ultrasound-triggered anti-inflammatory microbubbles have been developed to provide both imaging and therapeutic effects.¹ These microbubbles, loaded with anti-inflammatory agents, can be selectively activated at the thrombus site through ultrasound stimulation, enabling controlled drug release and real-time monitoring of thrombus-associated inflammation.

Despite these advancements, challenges remain in optimizing the efficacy and specificity of inflammation-targeted thrombolytic strategies.¹⁰⁷ Improving the precision of thrombotic microenvironment modulation is essential for minimizing off-target effects and improving therapeutic outcomes.¹⁰⁸ Additionally, the long-term safety and biocompatibility of NET-targeted nanoparticles and microbubble formulations require further investigation.¹⁰⁹ Future research should focus on refining delivery systems to respond dynamically to inflammatory signals and integrating multi-modal imaging techniques for comprehensive thrombus characterization.¹¹⁰ By addressing these challenges, inflammation-targeted theranostic strategies hold significant potential for advancing thrombus management and improving clinical outcomes in thrombin inflammatory disorders.

Nano-Based Thrombosis Therapy

Thrombosis is a complex and dynamic pathological process that progresses through multiple stages, including initiation, propagation, and resolution. Thrombosis can cause many diseases (Table 2). The advent of integrated nano-based delivery systems has introduced a closed-loop approach that seamlessly links diagnosis and treatment, thereby enhancing therapeutic efficacy while minimizing systemic side effects.^111,112 These advanced systems utilize multifunctional nanoplatforms to improve the precision and adaptability of thrombosis management.

Table 2 Diseases Caused by Thrombus

A fundamental component of these systems is intelligent diagnosis, which integrates advanced imaging modalities, biosensors, and real-time monitoring techniques. These technologies facilitate early detection, precise localization, and continuous assessment of thrombus evolution, enabling timely therapeutic intervention.¹¹³ Concurrently, targeted therapy is achieved through nanocarriers specifically designed to interact with thrombosis-associated components, such as fibrin networks, activated platelets, coagulation factors, and inflamed vascular endothelium.^114,115 By enhancing drug accumulation at the thrombotic site, these systems improve treatment efficacy while minimizing off-target effects. To enable real-time and synergistic modulation of the thrombotic microenvironment, advanced nano-systems are increasingly being engineered to both sense pathological cues and initiate targeted therapeutic responses. A notable example involves polydopamine-based nanomotors designed for the treatment of inferior vena cava thrombosis.¹¹⁶ These nanomotors feature a mesoporous polydopamine core that serves as a photothermal-responsive matrix. Upon near-infrared (NIR) irradiation, the system generates localized heat to enhance thrombus dissolution while simultaneously propelling the nanomotors to penetrate deeper into vascular tissue. In parallel, the nanomotors are loaded with the fibrinolytic agent urokinase and functionalized with RGD peptides for thrombus-specific recognition. Moreover, the RGD motif interacts with elevated levels of reactive oxygen species (ROS) in the thrombotic niche to catalyze the generation of nitric oxide (NO)—a multifunctional molecule that not only augments nanomotor propulsion but also promotes endothelial regeneration. Through this multifunctional design, the nanosystem achieves spatiotemporally controlled drug release, targeted navigation, and concurrent regulation of inflammatory and pro-thrombotic signals, exemplifying a closed-loop theranostic strategy with strong translational promise. There are many integrated nano-therapy strategies for thrombosis management (Table 3).

Table 3 Comprehensive Nano-Therapy Strategies for Thrombosis Management

In addition to precise targeting, adaptive treatment strategies further optimize thrombosis management by enabling controlled drug release in response to pathological cues. Stimuli-responsive nano-systems can react to microenvironmental factors such as pH variations, reactive oxygen species, enzymatic activity, or shear stress, ensuring on-demand therapeutic action aligned with disease progression.¹¹⁷ Through the integration of these capabilities, nano-based platforms present a promising strategy for both acute and chronic thrombosis management, which will be explored in the following sections.

Application in Acute Phase

Acute thrombosis is marked by rapid platelet aggregation, activation of coagulation factors, and fibrin network formation, leading to vascular occlusion and potentially life-threatening complications.^118–121 The primary therapeutic objectives during this phase include prompt thrombolysis, platelet inhibition, and anticoagulation while minimizing the risk of hemorrhagic events. Nano-based integrated thrombosis management systems provide innovative strategies to achieve these goals by enhancing drug targeting, real-time monitoring, and controlled therapeutic release.¹²²

Targeted thrombolytic delivery systems have been developed to improve the precision and efficacy of clot dissolution.^123–126 These nanosystems are specifically engineered to interact with key thrombotic components, including fibrin, coagulation factors (eg, FXa, FIIa), and platelet membrane receptors (eg, GP IIb/IIIa). By promoting site-specific drug accumulation, these approaches minimize systemic exposure and reduce adverse effects.¹²⁷ For instance, stimuli-responsive nanoparticles sensitive to pH changes or shear stress can selectively release thrombolytic agents, such as tPA, at the thrombotic site, enhancing clot degradation while mitigating systemic bleeding risks.^128,129 A representative example is a platelet-mimetic nano platform functionalized with Annexin V and loaded with tPA, which selectively binds to phosphatidylserine-exposing activated platelets at the thrombus site, as shown in Figure 4A.¹³⁰ This biomimetic system significantly improved thrombolytic efficacy and neurological outcomes in a mouse model of acute ischemic stroke, while reducing the risk of intracerebral hemorrhage.

Figure 4 (A)Schematic of APLT-PA preparation and thrombus-targeted therapy for acute stroke. APLT-PA was prepared via freeze–thaw and thin-film hydration, with platelet membranes and Annexin V enabling Ca²⁺-responsive targeting and thrombolysis in ischemic stroke mice. Reprinted from Quan X, Han Y, Lu P, et al. Annexin V-Modified Platelet-Biomimetic Nanomedicine for Targeted Therapy of Acute Ischemic Stroke. Adv Healthcare Mate. 2022;11(16):2200416. © 2022 Wiley-VCH GmbH.¹³⁰ (B). Schematic of supramolecular nanomedicine for vascular injury therapy. Constructed via α-CD–PEG-peptide interactions, NP@PBA&NO inhibits platelet activation and smooth muscle cell responses, reducing thrombosis and intimal hyperplasia. Reprinted from Zhou K, Huang C, Li J, et al. Multifunctional NO supramolecular nanomedicine for thrombus risk reduction and intimal hyperplasia inhibition. J Mater Chem B. 2025;13(5):1811–1822. Copyright Royal Society of Chemistry.²⁵

Beyond drug delivery, intelligent imaging and theranostic platforms play a critical role in acute thrombosis management by enabling real-time thrombus detection and treatment monitoring.^131–134 Nanoprobes incorporating fluorescence, magnetic resonance imaging (MRI), or photoacoustic imaging (PAI) modalities facilitate high-resolution visualization of thrombus formation, supporting timely clinical decision-making.^135–138 A notable example includes platelet membrane-coated nanoparticles loaded with superparamagnetic iron oxide (SPIO), which enhance MRI/PAI contrast while providing simultaneous diagnostic and therapeutic capabilities.^139,140

Additionally, mechanical stimulation and external stimulus-assisted therapies have emerged as promising strategies to enhance thrombolysis.^141–144 Nanocarriers integrated with mechanosensitive or externally activatable components, such as ultrasound-responsive nanobubbles, magnetic nanoparticles, or electrically charged drug carriers, facilitate clot dissolution upon activation.¹⁴⁵ For example, ultrasound-triggered nanobubbles can not only release thrombolytic agents but also exert mechanical disruption on the thrombus, improving clot degradation efficiency.¹⁴⁶

By integrating targeted drug delivery, intelligent diagnostics, and external stimulus-responsive strategies, nano-based thrombosis management systems represent a promising approach for improving thrombolytic efficacy while mitigating complications associated with conventional anticoagulant therapies.^147,148 These advancements lay the foundation for the next generation of personalized and adaptive interventions in acute thrombotic events.

Application in Chronic Phase

Chronic thrombosis is characterized by persistent inflammation, endothelial dysfunction, fibrosis, and vascular remodeling, all of which contribute to long-term complications and an increased risk of thrombus recurrence.^149–152 The primary therapeutic goals in this phase include preventing thrombosis, restoring endothelial function, and minimizing chronic vascular damage.¹⁵³ Nano-based therapeutic strategies offer innovative solutions by integrating anti-inflammatory, endothelial-regenerative, and long-acting anticoagulant approaches.

A key aspect of chronic thrombosis management involves nano-enabled anti-inflammatory and immunomodulatory therapies. Since inflammation-driven vascular injury plays a crucial role in thrombus recurrence, targeted drug delivery is essential for sustained vascular protection. Nanocarriers loaded with anti-inflammatory agents, such as interleukin-10 (IL-10) or transforming growth factor-beta (TGF-β) modulators, have been developed to mitigate vascular inflammation and promote endothelial homeostasis.^154–157 For instance, leukocyte membrane-coated nanoparticles (eg, neutrophil-mimicking nanoparticles) can home to inflamed sites, delivering small-molecule anti-inflammatory drugs or siRNA to suppress atherosclerosis-associated thrombotic risk.^158,159 An illustrative example involves a supramolecular nanomedicine co-delivering nitric oxide and antioxidants via a cyclodextrin-based system, enabling targeted accumulation at vascular injury sites, as shown in Figure 4B.²⁵ By synergistically reducing oxidative stress and enhancing NO-mediated endothelial repair, this platform effectively mitigated thrombotic risk and intimal hyperplasia, offering a versatile approach for chronic vascular inflammation control.

Beyond inflammation control, targeted endothelial repair strategies are critical for mitigating chronic thrombosis risk.^160–162 Nanotherapeutics designed to improve endothelial cell (EC) proliferation and function facilitate vascular healing and reduce long-term complications. Nanocarriers encapsulating vascular endothelial growth factor (VEGF), NO donors, or microRNAs have been shown to promote endothelial regeneration and restore vascular integrity. By improving EC function, these nanosystems stabilize the vascular environment, thereby reducing the likelihood of recurrent thrombotic events.^163,164

Long-acting anticoagulant and antiplatelet nano delivery systems provide another promising approach for chronic thrombosis management.^165–167 Conventional anticoagulant therapies often require frequent dosing, increasing the risks of systemic bleeding. In contrast, nanoformulations enable controlled, site-specific drug release triggered by pathological stimuli such as pH shifts, enzymatic activity, or reactive oxygen species (ROS). For example, self-regulating antiplatelet nanoparticles can release therapeutic agents such as aspirin or clopidogrel in response to high-shear stress conditions, ensuring localized and sustained antithrombotic effects while minimizing systemic adverse reactions.^168,169

By integrating anti-inflammatory modulation, endothelial repair, and stimulus-responsive anticoagulant delivery, nano-based thrombosis management systems provide a multifaceted approach to reducing the long-term burden of thrombotic diseases.¹⁷⁰ These advancements hold significant potential for preventing recurrent thrombotic events and improving vascular health in patients with chronic thrombosis.

Conclusion

Integrated nano-enabled systems for thrombosis management represent a significant advancement in the diagnosis and treatment of thrombotic disorders. By integrating intelligent diagnostics, targeted therapeutics, and real-time feedback mechanisms, these platforms improve treatment precision while minimizing systemic toxicity. Key innovations in endothelial injury targeting, platelet modulation, coagulation factor regulation, red blood cell–thrombus interactions, fibrinolysis, and inflammation control have demonstrated substantial potential for managing both acute and chronic thrombosis.

Despite these advances, several challenges impede clinical translation. Major barriers include concerns about biocompatibility, potential immunogenicity, long-term toxicity, and suboptimal thrombus-targeting specificity. Moreover, the scalability and reproducibility of nanocarrier fabrication, along with stringent regulatory requirements, pose significant obstacles to widespread clinical adoption.

Future Perspectives

To enable clinical translation, future research must overcome current limitations through technological innovation and interdisciplinary collaboration. One key challenge in translating Smart Thrombosis Care platforms into clinical practice lies in integrating these technologies into conventional workflows, which still rely heavily on anticoagulants and standard diagnostic tools.¹⁷¹ Demonstrating superior efficacy, safety, and cost-effectiveness over conventional strategies is essential for regulatory and clinical acceptance.

Personalized treatment strategies enabled by artificial intelligence (AI) and machine learning hold considerable promise.^172,173 These technologies can analyze patient-specific thrombotic profiles—including clot location, fibrin composition, and systemic biomarkers—to guide individualized drug selection, dosing, and release schedule.¹⁷⁴ Such algorithm-assisted optimization could substantially improve therapeutic outcomes while minimizing adverse effects.

Biomimetic nanotechnology, particularly the development of cell membrane-coated nanoparticles, offers further potential by enhancing immune evasion and targeting specificity.¹⁷⁵ Meanwhile, stimuli-responsive and programmable drug delivery systems capable of adjusting therapeutic release in response to environmental signals (eg, pH, ROS, thrombin) may enable precise, on-demand treatment in dynamic thrombotic microenvironments.

In addition, multimodal theranostic platforms integrating real-time imaging modalities such as PET or MRI with targeted nano therapy could enhance diagnostic accuracy and allow for spatiotemporally controlled drug delivery. RNA-based strategies—such as siRNA- and mRNA-loaded nanoparticles—also present new opportunities for endothelial protection and thrombus resolution at the genetic level.

Ultimately, the advancement of these technologies will require close collaboration among materials scientists, biomedical engineers, computational biologists, clinicians, and regulatory bodies.¹⁷⁶ Establishing standardized protocols for nanoparticle characterization, safety assessment, and clinical validation will be critical to ensuring reproducibility and accelerating clinical translation. Through such coordinated efforts, nano-based thrombosis management systems have the potential to reshape the future of personalized medicine for thrombotic disorders.

Disclosure

The authors report no conflicts of interest in this work.

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