Nanotechnology-Based Detection of Advanced Glycation and Products for Early Diagnosis of Chronic Diseases

Nanotechnology-Based Detection of Advanced Glycation and Products for Early Diagnosis of Chronic Diseases

Zeeshan rafi1*, Mariyam Rafi1, Tahseen Fatima1, Mohammad Mohsin Khan1

1Department of Bioengineering Integral University, Lucknow (U.P.)-India-226026. Email: zeddqazi@gmail.com, mariyamrafi2803@gmail.com, tahseen9554@gmail.com, mmohsiniul@gmail.com

*Corresponding Author Dr. Zeeshan Rafi

Department of Bioengineering Integral University, Lucknow (U.P.)-India-226026. Email: zeddqazi@gmail.com, mariyamrafi2803@gmail.com

Abstract

Advanced Glycation End Products are key biomarkers in chronic diseases such as diabetes, Alzheimers, and cardiovascular diseases, necessitating sensitive and early detection methods. Nanotechnology has revolutionized biosensing by utilizing nanomaterials like gold nanoparticles, carbon dots, and quantum dots to develop highly sensitive and selective biosensors for AGE detection in biological samples. This review explores the mechanisms, advantages, and applications of these

nanomaterial-based biosensors, highlighting their superior sensitivity over traditional methods like ELISA and HPLC. By enabling rapid, non-invasive diagnostics, these technologies facilitate early diagnosis and personalized management of chronic diseases, significantly improving patient outcomes.

Keyword(s):

nanotechnology; advanced glycation end products; biosensors; gold nanoparticles; carbon dots; quantum dots; diabetes; Alzheimers; cardiovascular diseases; early diagnosis

1. Introduction

   Advanced Glycation End Products (AGEs) are formed through non-enzymatic glycation of proteins, lipids, and nucleic acids, contributing significantly to the

   pathogenesis of chronic diseases, including diabetes, Alzheimers, and cardiovascular diseases [1]. The accumulation of AGEs in tissues and biological fluids promotes oxidative stress, inflammation, and tissue damage, making their early detection critical for timely intervention and effective disease management [2]. Traditional detection methods, such as enzyme-linked immunosorbent assays (ELISA) and high-performance liquid chromatography (HPLC), are limited by low sensitivity, high costs, lengthy processing times, and complex sample preparation requirements [3]. These limitations hinder their use in routine clinical diagnostics, particularly for detecting low AGE concentrations in early disease stages.

   Nanotechnology has emerged as a transformative solution, offering highly sensitive, rapid, and cost-effective biosensing platforms [4]. Nanomaterials such as gold nanoparticles (AuNPs), carbon dots (CDs), and quantum dots (QDs) possess unique physicochemical properties, including high surface-to- volume ratios, tunable optical characteristics, and robust signal amplification capabilities [5]. These properties enable the development of biosensors that detect AGEs at nanomolar concentrations, significantly surpassing the

   micromolar detection limits of traditional methods [6]. Furthermore, nanotechnology supports non-invasive sampling and point- of-care diagnostics, enhancing accessibility and patient comfort [7].

   This review comprehensively examines the role of nanotechnology in AGE detection, focusing on the use of AuNPs, CDs, and QDs in developing sensitive biosensors. It explores their applications in the early diagnosis of diabetes, Alzheimers, and cardiovascular diseases, emphasizing their superior sensitivity and specificity compared to conventional methods. The review also addresses challenges, such as nanomaterial toxicity and regulatory hurdles, and outlines future prospects for integrating these biosensors into clinical practice, supported by a robust set of references from review articles, research articles, and book chapters.

2. Nanomaterials in AGE Biosensing

   Nanomaterials have transformed biosensing by offering exceptional sensitivity and selectivity due to their unique optical, electrical, and chemical properties [4]. This section details the mechanisms and advantages of gold nanoparticles, carbon dots, and quantum dots in AGE detection, highlighting their

   role in advancing diagnostic capabilities

   (Table 1).

   1. Gold Nanoparticles

      Gold nanoparticles are widely utilized for their surface plasmon resonance (SPR) properties, which enable sensitive detection of biomolecular interactions through changes in optical absorbance [8]. AuNPs can be functionalized with AGE- specific antibodies or aptamers, ensuring selective binding in complex biological matrices [9]. A seminal study developed an AuNP-based colorimetric assay for AGE detection in serum, achieving a detection limit of 10 nM, a significant improvement over ELISAs 100 nM limit [10]. The assay leverages aggregation-induced SPR shifts upon AGE binding, producing a visible color change detectable with minimal instrumentation, ideal for point-of-care applications [11]. AuNPs biocompatibility and ease of synthesis enhance their scalability for clinical use [8]. Their versatility also supports integration into electrochemical and fluorescence-based platforms, broadening their diagnostic potential [12].

   2. Carbon Dots

      Carbon dots are fluorescent, carbon-based nanomaterials known for their high quantum yields, photostability, and biocompatibility [13]. Their surfaces can

      be modified with functional groups to selectively bind AGEs, enabling fluorescence-based detection [14]. A study reported a CD-based biosensor for AGE detection in saliva, achieving a detection limit of 5 nM and demonstrating high specificity against interfering biomolecules like glucose and albumin [15]. CDs are particularly advantageous for non-invasive diagnostics, as they detect AGEs in accessible fluids like saliva and urine [16]. Their cost-effective, eco-friendly synthesis from natural precursors makes them suitable for large-scale clinical applications [13]. Additionally, CDs tunable emission properties enable multiplexing, allowing simultaneous detection of multiple AGE isoforms, critical for comprehensive disease profiling [17].

   3. Quantum Dots

      Quantum dots are semiconductor nanoparticles with size-dependent fluorescence properties, offering high brightness, photostability, and narrow emission spectra [18]. These characteristics make QDs ideal for fluorescence resonance energy transfer (FRET) assays, which are highly sensitive to low analyte concentrations [19]. A study developed a QD-based FRET assay for AGE detection in plasma, achieving a detection limit of 2 nM, surpassing

      traditional methods [20]. By conjugating QDs with AGE-specific ligands, the assay detects AGEs through energy transfer, amplifying the fluorescence signal [21]. QDs ability to target multiple AGE isoforms simultaneously enhances their utility in understanding disease-specific AGE profiles, particularly in complex diseases like Alzheimers [20]. However, their potential toxicity, due to heavy metal content, requires careful design to ensure biocompatibility [18].

      Table 1: Comparison of Nanomaterial- Based Biosensors for AGE Detection

      AGEs are central to diabetic complications, including nephropathy, retinopathy, and neuropathy, by promoting inflammation and oxidative stress [22]. Early detection of AGEs in biological fluids can predict disease progression and guide therapeutic strategies. AuNP-based biosensors have been employed to detect AGEs in urine, offering a non-invasive alternative to blood tests [10]. A study demonstrated a CD-based fluorescenc sensor for real-time AGE monitoring in diabetic patients, achieving a sensitivity 10-fold higher than HPLC, with a

      detection limit of 5 nM [23]. This sensors

      Nanomaterial Type

      Detection Limit (nM)

      Sample Type

      abiDlietytetcotiodnetect AGKEesyinAdsavlaivnataegnehsances

      Method

      Gold Nanoparticles	10	Serum Cnonlo-irnimvaestirvice mRoanpitiodraingd lab[e1l-6f]r.ee
      Carbon Dots	5	Saliva FidluenotriefsycienngceelevaNteodn-AinGvaEsivlevaenlsd befor clinical symptocmosst-effmecatnivifeest, the
      Quantum Dots	2	Plasma FRET High sensitivity and

      patient compliance by enabling frequent,

      By e se

      biosensors facilitmatueltiepalerlxyinginterventions, such as lifestyle modifications or

3. Applications in Chronic Disease Diagnosis

   Nanotechnology-based AGE detection offers transformative potential for early diagnosis and monitoring of chronic diseases. This section explores its applications in diabetes, Alzheimers, and cardiovascular diseases, highlighting how these biosensors enable timely interventions.

   1. Diabetes

      pharmacological treatments, reducing the risk of severe complications [24].

   2. Alzheimers Disease

      AGEs contribute to Alzheimers disease by promoting amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation [25]. Detecting AGEs in cerebrospinal fluid (CSF) or blood can aid early diagnosis, critical for initiating therapies before irreversible neuronal damage occurs. QD-based FRET sensors

      have shown exceptional promise, detecting AGEs in CSF with a detection limit of 1 nM, surpassing ELISAs sensitivity [20]. Another study developed an AuNP-based electrochemical sensor for AGEs in serum, reporting high specificity in Alzheimers patients and a detection limit of 12 nM [26]. These biosensors enable early identification of at-risk individuals, supporting clinical trials for disease- modifying therapies [27]. Non-invasive detection in blood or saliva could further enhance their applicability for population- wide screening [28].

   3. Cardiovascular Diseases

      AGEs contribute to vascular stiffness, endothelial dysfunction, and atherosclerosis in cardiovascular diseases, making their detection vital for assessing disease risk [29]. Nanomaterial-based biosensors offer rapid and sensitive AGE detection in plasma, enabling early diagnosis and monitoring of treatment efficacy. A CD-based fluorescence sensor achieved a detection limit of 8 nM for AGEs in cardiovascular patients, providing insights into disease progression [30]. Similarly, AuNP-based electrochemical sensors have been used to monitor AGE levels in real-time, correlating with cardiovascular risk markers [26]. These technologies support personalized medicine by enabling tailored

      interventions based on individual AGE profiles, potentially reducing morbidity and mortality from cardiovascular events [31].

4. Advantages Over Traditional Methods

   Nanotechnology-based biosensors offer significant advantages over traditional methods like ELISA and HPLC, revolutionizing AGE detection. These advantages are critical for their adoption in clinical diagnostics and are detailed below:

   • Higher Sensitivity: Nanomaterials amplify detection signals, achieving nanomolar detection limits compared to micromolar limits of traditional methods [10]. For instance, QD-based FRET assays detect AGEs at 1 nM, enabling earlier diagnosis than ELISAs 100 nM limit [20]. This sensitivity is crucial for detecting low AGE concentrations in early disease stages [32].

   • Rapid Detection: AuNP-based colorimetric assays provide results within minutes, compared to hours for HPLC [8]. This speed is essential for point-of-care diagnostics, allowing immediate clinical decision-making [33].

   • Non-Invasive Sampling: CD- based sensors enable AGE detection in saliva and urine, reducing patient discomfort and facilitating frequent monitoring [15]. Traditional methods often require invasive blood draws, limiting their practicality [34].

   • Cost-Effectiveness: CDs and AuNPs are inexpensive to synthesize, unlike the costly reagents and equipment needed for HPLC [13]. This scalability supports widespread clinical adoption, particularly in resource- limited settings [35].

   • Multiplexing Capability: QDs narrow emission spectra allow simultaneous detection of multiple AGE isoforms, providing comprehensive disease profiles that ELISA cannot achieve [20]. This capability is vital for understanding complex diseases like Alzheimers [36].

   • Miniaturization and Portability: Nanomaterial-based biosensors can be integrated into portable devices, enabling point-of-care testing in clinics or homes [23]. Traditional methods require specialized

   laboratory infrastructure, limiting their accessibility [37].

   Despite these advantages, challenges such as nanomaterial toxicity, reproducibility, and regulatory approval must be addressed to ensure clinical translation [4].

5. Challenges and Limitations

   While nanotechnology-based AGE biosensors offer significant advantages, several challenges must be addressed to ensure their clinical utility. First, nanomaterial toxicity, particularly for QDs containing heavy metals like cadmium, remains a concern [18]. Surface modifications can enhance biocompatibility, but long-term safety in vivo requires further investigation [38]. Second, reproducibility of sensor performance across diverse biological samples (e.g., serum, plasma, saliva, urine) is challenging due to matrix effects and interfering biomolecules [39]. Standardized functionalization protocols and robust calibration methods are needed to ensure consistent results [40]. Third, regulatory approval for nanomaterial- based diagnostics is complex, requiring extensive validation of safety, efficacy, and reproducibility [41]. Current regulatory frameworks are not fully adapted to nanotechnology, necessitating updated guidelines [42]. Finally, scalability and

   cost of large-scale production must be optimized to make these biosensors accessible in low-resource settings [43]. Addressing these challenges through collaborative efforts will be essential for clinical adoption.

6. Future Prospects

   The future of nanotechnology-based AGE detection lies in integrating these biosensors with advanced technologies to enhance their clinical impact. Wearable devices incorporating CD-based sensors could enable continuous AGE monitoring in diabetic patients, providing real-time data for dynamic treatment adjustments [23]. Microfluidic and lab-on-a-chip platforms could miniaturize biosensors, enabling point-of-care testing in resource- limited settings [30]. Machine learning algorithms could enhance data analysis by identifying patterns in AGE profiles, improving diagnostic accuracy and predicting disease progression [44]. For example, integrating QD-based sensors with artificial intelligence could enable personalized risk stratification in Alzheimers patients [45]. Advances in biocompatible nanomaterial synthesis, such as green synthesis methods for CDs, could address toxicity concerns and facilitate regulatory approval [13]. Standardization of nanomaterial properties, such as size and surface chemistry, is

   critical to ensure reproducibility [46]. International collaborations to establish regulatory frameworks will accelerate the translation of these technologies into clinical practice, potentially transforming chronic disease management [47].The workflow of nanomaterial-based biosensors, including gold nanoparticles, carbon dots, and quantum dots, is illustrated in Figure 1.

   sensitivity, specificity, and practicality. These technologies surpass traditional methods like ELISA and HPLC by achieving nanomolar detection limits, rapid results, and non-invasive sampling capabilities. Their applications in early diagnosis of diabetes, Alzheimers, and cardiovascular diseases highlight their potential to enable timely interventions and improve patient outcomes. While challenges such as nanomaterial toxicity, reproducibility, and regulatory hurdles persist, ongoing research in biocompatible materials, standardized protocols, and advanced integration with wearable and AI-driven platforms promises to overcome these barriers. Nanotechnology-based AGE detection represents a paradigm shift in chronic disease diagnostics, paving the way for personalized medicine and enhanced healthcare delivery.

   Figure. 1 Nanomaterial-Based Biosensor Workflow for AGE Detection

7. Conclusion

Nanotechnology-based biosensors, leveraging gold nanoparticles, carbon dots, and quantum dots, have revolutionized the detection of Advanced Glycation End Products, offering unprecedented

Acknowledgment

The author acknowledges the contributions of researchers in nanotechnology and glycation studies whose work has informed this review. No specific funding was received for this article.

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