Gold nanomaterials in the diagnosis and treatment of kidney diseases: from fundamental transport mechanisms to clinical translation prospects

Introduction

As global population aging intensifies, coupled with the rising incidence of metabolic diseases such as diabetes and hypertension, kidney disease has evolved into a global publichealth challenge. Both acute kidney injury (AKI), which carries a high risk of mortality, and chronic kidney disease (CKD), characterized by a protracted course and propensity to progress to end-stage renal disease, present formidable challenges to existing clinical diagnostic and therapeutic modalities. Currently, clinical assessment of renal function remains heavily reliant on biochemical indicators such as serum creatinine and blood urea nitrogen. However, these markers exhibit significant lag in reflecting early kidney injury and fail to provide anatomical information (Ning et al., 2024; Yu et al., 2016). At the therapeutic level, conventional small-molecule drugs often face limitations including rapid systemic metabolism, poor local accumulation in the kidneys, and systemic toxicity resulting from non-specific distribution.

The advent of nanomedicine offers a promising avenue to overcome these hurdles. Among various nanomaterials, gold nanoparticles (AuNPs), a class of noble metal nanomaterials with controllable sizes (1–100 nm), have demonstrated substantial potential in renal precision medicine due to their unique physicochemical properties and favorable biocompatibility (Dykman and Khlebtsov, 2011; Yeh et al., 2012; Ashraf et al., 2016; Shukla et al., 2012; Delong et al., 2010). First, their surface plasmon resonance effect endows AuNPs with exceptional optical properties, applicable in colorimetric detection, photothermal therapy, and photoacoustic imaging (Eustis and el-Sayed, 2006). Second, their high surface area-to-volume ratio facilitates the loading of antibodies, aptamers, or drug molecules, enabling targeted recognition and precise delivery (Jain et al., 2006). Furthermore, surface modification strategies, such as PEGylation or protein coating, significantly enhance the biocompatibility and circulatory stability of AuNPs (Delong et al., 2010). Their high atomic number, conferring excellent X-ray attenuation capability, also positions them as high-performance CT contrast agents (Au et al., 2013; Kim et al., 2007). More importantly, by precisely controlling the size (Zhou et al., 2011; Naz et al., 2016) and surface charge (Ning et al., 2017; Huang Y. et al., 2024) of AuNPs, their distribution and metabolic behavior within the kidneys can be directionally modulated, establishing a physicochemical foundation for precision diagnosis and therapy of kidney diseases.

Leveraging these advantages, AuNPs have witnessed rapid development in theranostic applications for kidney diseases. However, the majority of existing reviews focus on the cataloguing of applications, often without a critical appraisal of the translational bottlenecks. This review distinguishes itself by providing a kinetic centric and barrier focused analysis of AuNP transport that explicitly considers the inter organ crosstalk between the liver and kidney—the so called liver kidney axis—as a major determinant of in vivo fate (Qi et al., 2024). Furthermore, building upon previous foundational toxicity studies of gold nanoparticles (Paul et al., 2018; Jawaid et al., 2020), we systematically deconstruct the conflicting in vivo data on AuNP nephrotoxicity, offering a mechanistic framework to reconcile these discrepancies and underscore the urgent need for standardized assessment protocols. By juxtaposing preclinical efficacy data against the stringent demands of clinical practice, we aim to provide a balanced perspective on the path forward for AuNP based renal nanomedicine. In diagnostics, AuNPs are widely utilized in optical imaging, CT imaging, surface-enhanced Raman scattering (SERS), and multimodal imaging, significantly enhancing the sensitivity and specificity of early kidney injury detection. Therapeutically, AuNPs serve as drug/gene delivery vehicles, photothermal/photodynamic therapeutic agents, and direct therapeutic nanomedicines, offering novel interventional strategies for diverse conditions such as AKI, CKD, renal fibrosis, and renal cell carcinoma. This review aims to systematically summarize the transport kinetics of gold nanomaterials across renal physiological barriers, consolidate Frontier research progress in their application for kidney disease diagnosis and treatment, analyze the key challenges related to biosafety and clinical translation, and provide perspectives on future research directions.

Before delving into renal transport kinetics, it is useful to briefly note the synthesis and key properties of gold nanomaterials that underpin their biomedical utility. Gold nanoparticles are most commonly prepared by chemical reduction of chloroauric acid using citrate (Turkevich method) or thiol-containing capping agents (Brust–Schiffrin method), with green synthesis using plant extracts emerging as an alternative route (Das et al., 2019). Their distinctive localized surface plasmon resonance (LSPR) enables colorimetric sensing and photothermal conversion, while the high atomic number of gold (Z = 79) provides exceptional X-ray attenuation for CT imaging. Equally important, the gold surface is readily functionalized via thiol–gold chemistry, allowing the attachment of polyethylene glycol (PEG), targeting ligands, or zwitterionic coatings that modulate circulation time and renal clearance. These properties collectively establish AuNPs as versatile platforms for renal theranostics, as elaborated in the following sections.

Renal physiological barriers and the kinetic behavior of gold nanomaterials

The efficacy of gold nanomaterials in renal applications is intricately linked to their in vivo transport and metabolic kinetics, with the unique physiological structure of the kidney constituting the primary barrier to their metabolism.

The glomerular filtration barrier represents the first critical checkpoint determining whether nanomaterials can be eliminated via the kidneys. This barrier comprises fenestrated endothelial cells, the negatively charged glomerular basement membrane, and the filtration slits formed by podocytes. Research indicates that the renal clearance efficiency of nanomaterials is highly size-dependent; typically, ultrasmall gold nanoclusters with a hydrodynamic diameter of less than 5.5 nm can efficiently traverse the filtration barrier into the primary urine, thereby avoiding prolonged accumulation in the reticuloendothelial system of organs like the liver and spleen (Zhou et al., 2011; Zhang et al., 2014). For instance, Zhou et al. demonstrated that glutathione-coated ∼2 nm fluorescent nanoparticles exhibited highly efficient renal clearance, with clearance rates 10 to 100 times higher than those of other ligand-coated nanoparticles of similar size (Zhou et al., 2011). Beyond size effects, surface charge plays a critical selective role in the filtration process. Using a series of ultrasmall gold nanoparticles with precisely engineered surface charges, Huang et al. revealed that the proximal tubules and peritubular capillaries, rather than the glomerulus, constitute the primary charge barrier for the renal transport of charged nanoparticles. Their study found that nanoparticle retention in the proximal tubules is mediated by direct Coulombic interactions between positively charged surface ligands and the negatively charged microvilli of proximal tubules, rather than being determined by the overall zeta potential (Huang Y. et al., 2024). While positively charged nanoparticles may exhibit higher filtration rates due to electrostatic attraction, excessively strong interactions can also lead to podocyte structural damage.

Upon entering the bloodstream, AuNPs are rapidly coated with adsorbed plasma proteins, forming a protein corona that constitutes their biological identity and governs subsequent interactions with cells and organs (Wang et al., 2019; Das et al., 2025). The composition of this corona depends on nanoparticle size, shape, surface charge, and surface chemistry. For example, PEGylation or zwitterionic coatings reduce protein adsorption (the “stealth” effect), whereas positively charged or hydrophobic surfaces promote opsonization and rapid clearance (Wang et al., 2019). Critically, protein adsorption increases the effective hydrodynamic diameter of AuNPs. Particles originally small enough for glomerular filtration (<5.5 nm) may, after corona formation, exceed the renal clearance threshold and be redirected toward hepatic or splenic elimination (Das et al., 2025). Moreover, the corona can mask targeting ligands, compromising active targeting strategies. Therefore, precise control over AuNP surface chemistry—drawing on advances in synthesis and functionalization (Das et al., 2019)—is essential to preserve renal clearance and targeting capabilities.

To address this challenge, surface modification with zwitterionic ligands (Ning et al., 2017) or biomolecules like glutathione (Zhang et al., 2012) can effectively inhibit non-specific protein adsorption, thereby preserving the renal clearance characteristics of the particles. Ning et al. discovered that ligand length is a critical factor influencing the physiological stability and renal clearance of ultrasmall zwitterionic inorganic nanoparticles. Even a mere 0.4 nm increase in hydrodynamic diameter significantly enhanced physiological stability and altered the clearance pathway (Ning et al., 2017). Murthy et al. designed gold nanospheres with binary mixed-charge ligands that maintained their size upon incubation in fetal bovine serum, successfully avoiding adsorption of individual serum proteins (Murthy et al., 2013).

After passing the filtration barrier, gold nanomaterials encounter reabsorption by proximal tubular epithelial cells as they traverse the renal tubules. Although this reabsorption mechanism, based on endocytosis, may prolong the retention of nanomaterials within the kidney, it also presents a unique opportunity for targeted drug delivery to renal tubular epithelial cells (Huang et al., 2025a). Using renally-clearable luminescent gold nanoparticles surface-engineered to mimic the PEPT1/2-targeting Gly-Sar peptide, Huang et al. successfully demonstrated specific and highly efficient interactions with renal tubular cells in both in vitro and in vivo settings. This efficient transcellular transport can redirect nanoparticles back into the bloodstream via reabsorption, significantly enhancing their bioavailability and offering a novel strategy for tumor imaging (Huang D. et al., 2024). The intracellular behavior of nanoparticles is even more complex. Huang et al. observed that when the isoelectric point of pH-responsive, renally-clearable gold nanoparticles overlapped with the pH range of endosomes, they rapidly self-assembled into single nanospheres within the endosomes of proximal tubular epithelial cells. This “one assembly per endosome” phenomenon effectively delayed reactive oxygen species (ROS)-mediated biotransformation while preserving cellular function, suggesting that targeting the isoelectric point of nanomedicines could enable subcellular control over assembly and clearance processes (Huang et al., 2025b). Ding et al. found that under hypoxic conditions, the uptake of 5 nm AuNPs by HK-2 cells increased significantly, with excessive endocytosis leading to ROS production, reduced mitochondrial membrane potential, and induction of both apoptotic and autophagic cell death. This finding provides crucial insights into the potential risks associated with using AuNP-based therapies in patients with chronic kidney disease (Ding et al., 2014). Notably, Peng et al. reported that glutathione ligands could guide the selective growth of gold nanoparticles within mitochondria in biological tissues, potentially linked to the unique glutathione storage function of mitochondria. This discovery opens new avenues for tissue labeling and the future development of artificial biological-nanohybrid systems (Peng et al., 2020).

The in vivo fate of nanoparticles is not determined solely by the kidneys; hepatic metabolism significantly impacts their transport and clearance. Qi et al. discovered that when renally-clearable gold nanoclusters pass through the liver, despite minimal hepatic accumulation and strong resistance to serum protein binding, they undergo glutathione-mediated biotransformation on their surface, leading to ligand dissociation from the gold core. By analyzing these transformation “fingerprints” in urine, a urinary biotransformation index linearly correlated with hepatic glutathione levels could be established. This finding not only reveals previously unrecognized liver-kidney inter-organ interactions but also develops a non-invasive method for quantifying liver glutathione levels through simple urinalysis (Qi et al., 2024). In summary, the renal transport of gold nanomaterials is a multi-step, multi-barrier process involving size and charge selectivity during glomerular filtration, protein corona formation and modulation, tubular reabsorption and transcytosis, and intracellular self-assembly and biotransformation (Figure 1). A thorough understanding of these kinetic behaviors is essential for achieving the safe clinical application and precision medicine deployment of gold nanomaterials.

Application of gold nanomaterials in the diagnosis of kidney diseases

Leveraging their unique optical, CT, and photoacoustic properties, gold nanomaterials offer a powerful toolkit for non-invasive, precision diagnosis of kidney diseases.

In the realm of optical imaging, renally-clearable near-infrared (NIR) luminescent gold nanoparticles provide highly sensitive tools for renal function imaging. Yu et al. utilized such nanoparticles in a mouse model of unilateral obstructive nephropathy to achieve non-invasive staging of renal dysfunction, revealing adaptive functional changes undetectable by conventional biomarkers, thereby offering a sensitive and practical monitoring tool for preclinical research (Yu et al., 2016). Exploiting the renal microenvironment, Zhao et al. developed pH-responsive luminescent gold nanoparticles for the early diagnosis and monitoring of metabolic acidosis-induced kidney injury (MAKI). This probe facilitated pH-induced charge reversal and intrarenal self-assembly, enabling differentiation between early and late-stage MAKI within 10 min post-injection and effectively monitoring recovery after treatment in real-time (Zhao et al., 2024). Similarly, Tan et al. utilized pH-induced charge-reversing AuNPs to achieve enhanced ultrasound contrast in injured kidneys by augmenting tubular reabsorption and in situ aggregation, providing precise anatomical information for diagnosing early kidney injury (Tan et al., 2021). Advancing this concept, Zhao et al. developed an activatable luminescent AuNP based on an in vivo ligand exchange strategy. Using triphenylphosphine-3,3′,3″-trisulfonic acid-coated AuNPs that undergo ligand exchange with intracellular glutathione, they achieved significantly activated emission in the second near-infrared (NIR-II) window, suitable for sensitive and long-term non-invasive monitoring of acid-induced early kidney injury (Zhao et al., 2023). Beyond functional imaging, Hua et al. integrated renally-clearable luminescent AuNPs with silk films to construct an implantable temperature-sensing device. The fluorescence intensity exhibited a linear relationship with temperature, and the device showed extremely low in vivo residual levels with no adverse effects over 8 weeks, demonstrating its potential for in vivo temperature monitoring (Hua et al., 2020).

Surface-enhanced Raman scattering (SERS) technology demonstrates significant potential for non-invasive liquid biopsy. Espinosa et al. utilized citrate-reduced AuNPs to enhance urinary SERS signals. Combined with partial least squares discriminant analysis (PLS-DA), this approach successfully distinguished lupus nephritis patients from healthy controls with 97.6% accuracy, and could detect nephritis features up to 2 years before clinical diagnosis, revealing metabolic pathway disturbances during lupus nephritis (Espinosa et al., 2025). Another study employed AuNP-enhanced SERS combined with PLS-DA to differentiate hypertensive patients, specifically identifying those with concomitant kidney injury with 100% sensitivity (Espinosa-Garavito et al., 2024). In methodological explorations, Aitekenov et al. compared different substrates for detecting proteinuria, finding that 100 nm AuNPs on a silver substrate performed optimally. They also reported the first application of a silicon substrate for direct SERS detection of proteins in biofluids, offering a new approach for low-cost, efficient diagnostics (Aitekenov et al., 2023). For detecting creatinine, a key indicator of renal function, Chen et al. constructed three-dimensional ribbon-like AuNP assemblies on MXene surfaces, achieving a detection limit as low as 2.64 nM in aqueous solutions, providing a highly sensitive new method for clinical diagnosis (Chen et al., 2025).

Colorimetric detection methods based on AuNP aggregation-induced color changes have led to the development of several point-of-care testing tools due to their simplicity and cost-effectiveness. Kuang et al. utilized 18-crown-6 ether-functionalized AuNPs to form cavity complexes with amines, enabling rapid and sensitive detection of melamine with a detection limit of 6 ppb (Kuang et al., 2011). For renal function markers, Du et al. developed a colorimetric method for creatinine detection suitable for home-based renal function monitoring, leveraging synergistic coordination between creatinine and Hg²⁺ (Du et al., 2015). Zhang et al. utilized the Tyndall effect triggered by creatinine-induced crosslinking and aggregation of AuNPs, coupled with a smartphone, to achieve quantitative creatinine detection with a detection limit of 0.084 μM (Zhang et al., 2024). Lee et al. designed a lateral flow immunoassay device with a herringbone pattern, enabling semi-quantitative detection of microalbuminuria by counting spots with the naked eye, achieving a detection limit of 15.5 μg/mL, suitable for resource-limited settings (Lee et al., 2020). Bikkarolla et al. developed a rapid quantitative lateral flow assay for cystatin C, demonstrating excellent stability and correlation with standard methods (Bikkarolla et al., 2024). Jin et al. developed a paper-based, enzyme-free uric acid detection device. Following protein precipitation from whole blood using Zn²⁺, a colorimetric reaction catalyzed by AuNPs allowed detection within 8 min, offering a new point-of-care tool for hyperuricemia-related renal syndromes (Jin et al., 2024). For more sensitive detection, Liu et al. developed charge-pairing, renally-clearable ratiometric chemiluminescent ROS nanoprobes that successfully detected pathological ROS non-invasively in several disease models. The charge-pairing strategy effectively inhibited recognition by the mononuclear phagocyte system, reducing hepatic retention of AuNPs by nearly 100-fold (Liu et al., 2025). Chang et al., using a 96-well plate-based localized surface plasmon-coupled fluorescence biosensor, provided the first evidence that urinary cofilin-1 levels are significantly elevated in AKI patients, suggesting a new potential biomarker for AKI diagnosis (Chang et al., 2014). In summary, the application of gold nanomaterials in kidney disease diagnosis spans a broad spectrum, from structural imaging to molecular detection, and from laboratory-based equipment to point-of-care devices. Their technological features, detection targets, and key performance indicators are summarized in Table 1.

TABLE 1. Representative applications of gold nanomaterials in kidney disease diagnosis.

While the studies summarized in Table 1 underscore the remarkable analytical performance of AuNP based diagnostics, a head to head comparison of these modalities reveals distinct translational trade offs. Surface enhanced Raman scattering (SERS) offers femtomolar sensitivity and rich molecular fingerprinting, yet its clinical deployment is severely hampered by the need for expensive, high precision instrumentation and the lack of standardized spectral libraries across laboratories. Colorimetric and lateral flow assays, in contrast, excel in point of care (POC) settings due to their low cost and instrument free readout; however, their quantitative accuracy and dynamic range are typically inferior, limiting their utility to screening rather than definitive diagnosis. Fluorescence and photoacoustic imaging provide real time functional and anatomical information but are constrained by tissue penetration depth and, in the case of CT, by cumulative radiation exposure. Therefore, a realistic clinical workflow is unlikely to rely on a single AuNP based modality. Rather, we envision a tiered approach: POC colorimetric strips for home based screening of high risk populations, followed by quantitative SERS or fluorescence urinalysis in clinical laboratories, and finally, targeted AuNP enhanced CT or PET imaging for precise anatomical localization and staging in confirmed cases. Addressing the reproducibility of nanoparticle synthesis, the stability of surface functionalization under storage conditions, and the regulatory classification of these hybrid nano diagnostics remain formidable, yet surmountable, challenges on the path to routine clinical use.

In the field of CT imaging, gold nanoparticles are considered ideal CT contrast agents due to their high X-ray attenuation coefficient. Kim et al. reported PEG-coated AuNPs with an X-ray absorption coefficient 5.7 times higher than conventional iodine-based agents, exhibiting significantly prolonged circulation time in vivo and generating approximately twice the tumor-to-normal tissue contrast in a rat liver tumor model (Kim et al., 2007). Au et al. synthesized methoxypolyethylene glycol thiol-coated AuNPs enabling clear visualization of the abdominal aorta and renal arteries for up to 24 h, compared to 6 h with conventional iodine agents, making them suitable for CT-guided interventional procedures (Au et al., 2013). Aziz et al. compared porous and solid AuNPs, finding that porous AuNPs generated significantly higher contrast in CT scans (Aziz et al., 2017). By endowing AuNPs with active targeting capabilities, Zhu et al. utilized anti-collagen I antibody-conjugated AuNPs to achieve CT imaging-based assessment of renal fibrosis severity. In stenotic mouse kidneys, retention of targeted nanoparticles was significantly higher than in the contralateral kidney and correlated with collagen deposition, offering a novel approach for non-invasive quantitative assessment of tissue fibrosis (Zhu et al., 2018).

Combining AuNPs with other functional molecules enables complementary, multimodal imaging. Wang et al. designed a novel MR/CT/NIRF trimodal contrast agent incorporating PSMA1 ligands for specific detection of early-stage prostate cancer, demonstrating preferential PSMA targeting and favorable renal clearance behavior (Wang et al., 2023). Chen et al. developed ⁶⁴Cu-labeled renally-clearable AuNPs, utilizing dynamic positron emission tomography (PET) imaging to reveal their extremely rapid elimination kinetics, overcoming the depth limitations of optical imaging and the low temporal resolution of single-photon emission computed tomography (SPECT) (Chen F. et al., 2016). Nguyen et al. developed chain-like ultrasmall AuNP clusters providing red-shifted optical absorption in the NIR window. In a rabbit eye model, αvβ3 integrin-targeted gold nanoclusters (GNCs) significantly enhanced photoacoustic and optical coherence tomography (OCT) signals for choroidal neovascularization. Post-imaging, they could disassemble and be excreted via urine, demonstrating excellent biosafety (Nguyen et al., 2023). Morales-Dalmau et al. utilized two-photon luminescence microscopy to achieve sub-micrometer resolution quantitative analysis of gold nanorod distribution in tumors, kidneys, spleen, and liver. Their results showed high concordance with inductively coupled plasma mass spectrometry (ICP-MS), providing a powerful tool for understanding nanoparticle delivery mechanisms (Morales-Dalmau et al., 2019).

Finally, AuNP-assisted laser desorption/ionization mass spectrometry (LDI MS) provides a high-throughput platform for discovering novel disease biomarkers. Arendowski et al. analyzed urine from renal cell carcinoma (RCC) patients and healthy volunteers using AuNPET LDI MS, successfully identifying 15 metabolites significantly differentially expressed in RCC patients’ urine, offering a new diagnostic tool for non-invasive RCC detection (Arendowski et al., 2020). Subsequently, they performed metabolomic analysis on serum and urine from RCC patients, identifying potential biomarkers capable of distinguishing clear cell RCC, presence of metastasis, and different disease stages (Arendowski et al., 2021). Collectively, these studies demonstrate that gold nanomaterials, leveraging their unique optical, CT, and Raman-enhancing properties, have evolved into powerful tools for multifunctional imaging and biosensing in kidney diseases (Figure 2).

Application of gold nanomaterials in the treatment of kidney diseases

Beyond diagnostics, gold nanomaterials are being actively developed as therapeutic agents or delivery platforms for kidney diseases. We categorize these applications into three principal mechanistic classes: (i) drug and gene delivery vectors; (ii) photothermal/photodynamic effectors; and (iii) intrinsically bioactive renoprotective agents (Figure 2).

As drug and gene carriers, the high surface area and modifiability of AuNPs render them ideal delivery platforms. Peng et al. demonstrated the unique advantages of renally-clearable AuNPs in anticancer drug delivery. They found that renally-clearable AuNPs successfully retained the rapid tumor-targeting characteristics of free doxorubicin while accelerating the clearance of non-targeted molecules via renal excretion, addressing the “targeting-clearance” paradox in anticancer drug delivery (Peng et al., 2019a). Further studies revealed that compared to 30 nm non-renally-clearable carriers, 5 nm renally-clearable carriers exhibited a 2-fold increase in tumor accumulation, a 7-fold increase in therapeutic efficacy, and a 10-fold increase in therapeutic index. This suggests that leveraging ultra-high vascular permeability can further improve anticancer drug delivery without necessitating prolonged blood circulation (Peng et al., 2019b). In gene therapy, Chaudhary et al. utilized AuNPs to deliver the decorin gene, significantly reducing peritoneal dialysis-associated peritoneal fibrosis by downregulating the expression of TGF-β1, α-SMA, and VEGF, offering a promising new strategy for preventing peritoneal fibrosis (Chaudhary et al., 2014). Fang et al. developed targeted immunoliposomes modified with α8 integrin antibodies for specific targeting of glomerular mesangial cells, efficiently delivering dexamethasone and TGFβ1 siRNA to ameliorate glomerulonephritis in a murine model (Fang et al., 2022). Lai et al. reported a glutathione modified fluorescent AuNP and Co²⁺ induced self assembly platform that responds to acidic conditions to release Co²⁺ in a controlled manner, significantly alleviating renal fibrosis in a UUO model (Lai et al., 2020).

While the Co²⁺ release platform (Lai et al., 2020) demonstrates proof of concept efficacy, the potential nephrotoxicity of free cobalt ions—a known inducer of oxidative stress and hypoxia mimetic signaling—must be carefully weighed against the therapeutic benefit. This exemplifies a broader concern in renal nanomedicine: the carrier may be renally clearable and biocompatible, yet the payload itself could pose unforeseen risks, particularly in patients with pre existing compromised renal function. Future studies should include rigorous comparative toxicology of the carrier alone versus the drug loaded construct.

Liu et al. reported a novel dialysis membrane setup that quantified the kinetics of low-intensity pulsed ultrasound-triggered doxorubicin release from gold nanoparticles (GNPs). They identified acoustic radiation force as the primary driver of non-thermal release, with the release mechanism involving anomalous diffusion from the GNP surface, providing a theoretical basis for optimizing ultrasound-triggered drug delivery systems (Wang et al., 2025).

In photothermal therapy (PTT) and photodynamic therapy (PDT), the photothermal conversion properties of AuNPs offer new strategies for treating cancer and bacterial infections. For tumor therapy, Al-Barram et al. utilized GSH-modified small-sized AuNPs that leverage the pH difference between cancer cells and normal cells for selective targeting. Upon NIR laser irradiation, these nanoparticles effectively killed cancer cells, with their small size also facilitating renal clearance and reducing toxicity accumulation (Al-Barram, 2021). To enhance biosafety, Rengan et al. reported biodegradable liposomal gold nanoparticles that achieved complete tumor ablation in mice upon NIR laser irradiation, significantly extending disease-free survival. The nanoparticles could be degraded in situ within hepatocytes and cleared via hepatobiliary and renal pathways (Rengan et al., 2015). Singh et al. developed biodegradable glutathione-functionalized gold core-shell nanoparticles that, after exerting their photothermal effect, could disassemble into renally-clearable small gold seeds, showing no toxicity over 14 days (Singh et al., 2023). Exploiting the tumor microenvironment, Yuan et al. developed host-guest interaction-based renally-clearable AuNPs that undergo pH-responsive self-assembly within tumors, simultaneously enhancing photothermal therapy and chemotherapy effects against liver tumor microenvironments, enabling precise liver tumor treatment without damaging surrounding normal tissue (Yuan et al., 2025). Tourneur et al. discovered that pulsed laser irradiation of AuNPs could activate the autophagy pathway, leading to the elimination of renal cancer cells with high basal ROS levels. This highlights elevated ROS levels as a potential target for ROS-mediated cytotoxic therapies (Tourneur et al., 2025). In antimicrobial therapy, Zhou et al. constructed mixed-valence gold-porphyrin coordination networks. By integrating the direct bactericidal effect of ionic gold, ROS generated from the peroxidase-like activity of gold nanoclusters, and the photodynamic effect of porphyrin, they achieved multimodal antibacterial activity against E. coli and S. aureus. These networks exhibited broad-spectrum bactericidal efficacy and could be rapidly cleared via the kidneys post-treatment, demonstrating good biocompatibility (Zhou et al., 2023).

Remarkably, several studies indicate that AuNPs themselves, or those loaded with natural products, possess direct renoprotective effects. In mitigating AKI, Saleh et al. found that PEG-coated AuNPs dose-dependently reduced blood urea nitrogen (BUN) and creatinine levels, and decreased tubular atrophy, inflammation, and apoptosis in diabetic mice following renal ischemia-reperfusion injury, mediated through activation of the AMPK-Nrf2 signaling pathway (Saleh et al., 2022). Peres et al. demonstrated that AuNPs protected against tubulointerstitial injury in a mouse model of subclinical AKI by inducing an anti-inflammatory Th2 response and restoring megalin-mediated albumin endocytosis, without exhibiting nephrotoxicity in healthy mice (Peres et al., 2023). Siddiqui et al. found that N-(2-hydroxyphenyl) acetamide and its gold nanoformulation effectively reduced serum urea and creatinine levels, protected the actin cytoskeleton, and ameliorated glycerol-induced AKI through antioxidant and anti-inflammatory mechanisms (Siddiqui et al., 2019). In mitigating drug- or toxin-induced nephrotoxicity, numerous studies using plant extract-synthesized AuNPs have yielded positive outcomes. Adebayo et al. utilized Nymphaea lotus extract-synthesized AuNPs to significantly improve cadmium-induced alterations in renal function markers and inflammation in rats (Adebayo et al., 2023). Anadozie et al. confirmed that Hibiscus species-mediated AuNPs alleviated aluminum chloride-induced nephrotoxicity, downregulating the mRNA expression of pro-inflammatory factors (Anadozie et al., 2024). El-Sayed et al. demonstrated that Ficus carica leaf extract-loaded AuNPs significantly ameliorated cisplatin-induced AKI by scavenging ROS and enhancing antioxidant properties (El-Sayed et al., 2019). Hussein et al. confirmed that Moringa oleifera leaf extract-loaded AuNPs effectively alleviated cisplatin-induced oxidative stress and inflammation (Hussein et al., 2024). Wang et al. developed an arginine-liposome-amplified colorimetric immunoassay for cystatin C detection, successfully applying it to evaluate the protective effect of Astragalus against cisplatin-induced AKI (Wang et al., 2022). Additionally, Reshi et al. found that AuNPs dose-dependently reversed acetaminophen-induced hepato-renal injury and oxidative stress in rats (Reshi et al., 2017). Abd Elhameed et al. discovered that phthalocyanine-gold nanoconjugates effectively mitigated silver nanoparticle-induced hepato-renal toxicity through antioxidant, anti-apoptotic, and anti-inflammatory activities (Abd Elhameed et al., 2024). Dkhil et al. confirmed that AuNPs alleviated renal oxidative damage and histological alterations induced by Schistosoma mansoni infection, with effects linked to free radical scavenging mechanisms (Dkhil et al., 2016).

In improving diabetic nephropathy (DN), Alomari et al. reported that 50 nm AuNPs effectively alleviated proteinuria and glomerular basement membrane thickening in a rat model of DN by inhibiting podocyte injury and downregulating fibrotic markers such as TGF-β1 (Alomari et al., 2020). Al-Tantawy et al. found that AuNPs and dapagliflozin exhibited significant renoprotective effects in DN by targeting miR-192 and miR-21 and their downstream pathways (Al-Tantawy et al., 2023). Manna et al. demonstrated that pomegranate peel extract-stabilized AuNPs alleviated inflammation by modulating the MAPK/NF-κB/STAT3/cytokine axis and activated the PI3K/AKT-mediated Nrf2 antioxidant pathway, effectively reducing streptozotocin (STZ)-induced DN (Manna et al., 2019).

In adjuvant therapy and physical interventions, AuNPs also show diverse applications. Pedro et al. found that tumor necrosis factor-alpha (TNF-α)-coated AuNPs significantly enhanced the ablative effect of radiofrequency ablation (RFA) in a rabbit renal tumor model, resulting in a significantly larger zone of complete cell death (Pedro et al., 2010). In vitro studies by Nikzad et al. also indicated that radiofrequency radiation in the presence of AuNPs significantly reduced the viability of renal cancer cells, suggesting a potential alternative to nephrectomy (Nikzad et al., 2017). In hemodialysis, Chen et al. designed an artificial kidney system modified with AuNPs under resonant illumination. This system not only enhanced uremic toxin clearance efficiency through resonance excitation but also reduced protein adsorption and coagulation activation due to the negatively charged surface in the excited state. Furthermore, the solution generated by this system exhibited high free radical scavenging capacity, reducing dialysis-induced oxidative stress and renal fibrosis, offering an innovative strategy for CKD treatment (Chen H. C. et al., 2016). In vascular interventions, Barcena et al. incorporated AuNPs into polycaprolactone wraps, rendering them visible under micro-CT for long-term monitoring of mesenchymal stem cell-loaded wraps promoting arteriovenous fistula maturation. This confirmed the feasibility of using AuNPs as tracers without compromising therapeutic efficacy (Barcena et al., 2023). Liu et al. prepared temperature-sensitive poly (N-isopropylacrylamide-co-acrylic acid)-modified AuNPs with excellent X-ray attenuation capability and temperature-dependent sol-gel transition characteristics. These could form in situ casts within tumor vessels for embolization, offering more durable effects than conventional embolic agents, along with good biocompatibility (Liu et al., 2017). Representative studies of these therapeutic strategies are summarized in Table 2.

TABLE 2. Representative applications of gold nanomaterials in kidney disease treatment.

Implications for metabolism associated kidney diseases

The global rise in obesity, diabetes, and metabolic syndrome has made diabetic nephropathy (DN) and obesity related glomerulopathy the leading causes of CKD and end stage renal disease. In these pathological states, the renal microenvironment is profoundly altered by chronic hyperglycemia, dyslipidemia, and heightened oxidative stress—all of which can fundamentally alter the in vivo behavior of gold nanomaterials within the renal microenvironment.

Hyperglycemia promotes the non enzymatic glycation of serum proteins, which may modify the composition and conformation of the protein corona adsorbed onto AuNPs. Glycated albumin, for instance, exhibits altered binding affinity for nanoparticle surfaces and may redirect AuNPs toward scavenger receptors (e.g., RAGE) expressed on podocytes and tubular epithelial cells, potentially enhancing off target renal accumulation. Concurrently, early diabetic hyperfiltration could accelerate the glomerular sieving of small AuNPs, while later stage glomerulosclerosis would drastically impair clearance, leading to prolonged retention and increased risk of toxicity.

Several studies have directly evaluated AuNPs in DN models. Alomari et al. reported that 50 nm AuNPs attenuated albuminuria and podocyte injury in STZ induced diabetic rats, an effect linked to downregulation of TGF β1 and preservation of nephrin expression (Alomari et al., 2020). Manna et al. demonstrated that pomegranate peel extract stabilized AuNPs activated the Nrf2 antioxidant pathway while suppressing NF κB driven inflammation, thereby reducing glomerulosclerosis in DN (Manna et al., 2019). These findings suggest that AuNPs may possess intrinsic therapeutic activity that is particularly relevant in the pro oxidant, pro inflammatory milieu of metabolic kidney disease.

The same metabolic perturbations that drive disease progression could be exploited for diagnostic purposes. For example, pH responsive AuNPs (Zhao et al., 2024) could potentially detect the early tubular acidosis associated with diabetic ketoacidosis or chronic metabolic acidosis. Similarly, ROS sensitive AuNP probes (Liu et al., 2025) could provide a non invasive readout of renal oxidative stress, a hallmark of both diabetic and obesity related kidney injury.

The intersection of AuNP technology and metabolic kidney disease is an emerging Frontier. Future studies must systematically investigate how the metabolic milieu alters the nano bio interface, and conversely, how AuNP based theranostics can be engineered to exploit—rather than be thwarted by—these disease specific alterations. This is particularly critical given that a substantial proportion of patients who might eventually require these advanced nano-therapies will present with underlying renal impairment or metabolic dysfunction.

Biosafety, toxicity assessment, and challenges for clinical translation

Despite the promising applications of gold nanomaterials, their biosafety profile is a prerequisite for clinical translation.

Numerous studies indicate that the toxicity of AuNPs is intricately linked to their physicochemical properties. Regarding size dependence, studies by Abdelhalim et al. demonstrated that smaller GNPs induce more pronounced histological alterations in rat renal tubules (Abdelhalim and Jarrar, 2011a; Abdelhalim and Jarrar, 2011b). While Zhang et al. found that GSH protected ultrasmall nanoclusters exhibited complete and safe renal clearance (Zhang et al., 2012). These apparent discrepancies can be rationalized by considering the non linear relationship between particle size and renal exposure. Ultrasmall nanoclusters (<2 nm hydrodynamic diameter) behave akin to small molecules, passing freely through the glomerulus and being excreted in urine before significant endocytosis by tubular epithelial cells can occur. Nanoparticles in the 5–10 nm range, however, undergo substantial glomerular filtration followed by extensive reabsorption via megalin/cubilin mediated endocytosis in the proximal tubule, leading to high intracellular concentrations and, consequently, the greatest potential for cytotoxicity. Particles larger than ∼10–15 nm are largely excluded from glomerular filtration and are instead sequestered by the reticuloendothelial system, primarily in the liver and spleen, thereby sparing the kidneys from direct exposure. This “U shaped” relationship between size and nephrotoxicity underscores the importance of precisely controlling AuNP dimensions for renal applications.

Furthermore, the metric used to express dose—whether mass concentration (μg/mL), particle number (particles/mL), or total surface area (cm²/mL)—dramatically influences the interpretation of toxicity studies. Comparisons across studies that do not report and normalize by surface area or particle number are inherently fraught, highlighting the urgent need for standardized reporting guidelines in the field. A comprehensive comparison of these diverse toxicological findings is presented in Table 3.

TABLE 3. Summary of physicochemical properties and associated toxicity outcomes of gold nanoparticles.

Abdelrahman et al. also confirmed that 10 nm GNPs caused the most severe increases in renal function parameters and renal pathological changes, while quercetin exhibited significant nephroprotective effects (Abdelrahman et al., 2023). Long-term studies by Naz et al. on ultrafine AuNPs indicated they are primarily excreted via urine without causing systemic toxicity, supporting their safety profile in drug delivery systems (Naz et al., 2016). Concerning dose and time dependence, Xu et al. found that beyond a threshold dose, the pharmacokinetics of glutathione-coated AuNPs exhibited significant dose dependence, accelerating renal excretion and shortening blood retention. The no-observed-adverse-effect level (NOAEL) in mice exceeded 1,000 mg kg^-1, and no adverse effects were observed in non-human primates at high doses over 90 days (Xu et al., 2018). Almarshad et al. noted that intraperitoneal injection of AuNPs led to alterations in mouse erythrocyte parameters and signs of glomerular injury (Almarshad et al., 2025). Jarrar et al. observed histological damage in the kidneys, liver, heart, and lungs following repeated AuNP injections, suggesting functional risks to vital organs upon exposure (Jarrar et al., 2022). Surface chemistry plays a crucial role as well. Zhang et al. compared bovine serum albumin (BSA)- and glutathione (GSH)-protected Au nanoclusters, finding that GSH-protected clusters induced acute inflammation and kidney injury that completely resolved by day 28 due to efficient renal clearance. In contrast, BSA-protected clusters exhibited low clearance efficiency, accumulated in the liver and spleen, and led to irreversible toxic reactions (Zhang et al., 2012). Enea et al. investigated the effects of AuNPs with different sizes, shapes, and surface coatings on human kidney cells, finding that 13 nm nanoparticles with mercaptoundecanoic acid (MUA) coating exhibited the greatest toxicity, inducing apoptosis by increasing ROS, decreasing mitochondrial membrane potential, and activating caspases (Enea et al., 2020). Regarding long-term biodistribution and clearance, Jakic et al. conducted a 120-day long-term observation of BSA-coated AuNPs. Despite negligible amounts found in the kidneys, clearance from the liver and spleen was slow, and chronic exposure was associated with inflammatory and fibrotic responses in organs, particularly pronounced in the kidneys (Jakic et al., 2024).

At the molecular mechanism level, oxidative stress and inflammation are considered primary toxicity pathways. Alshammari et al. elucidated that AuNPs induce oxidative stress by triggering mitochondrial permeability transition pore opening, upregulating NOX4 expression, and inhibiting antioxidant enzyme activity. Concurrently, they activate the NF-κB signaling pathway, increasing pro-inflammatory cytokine levels and promoting inflammation, ultimately leading to glomerular and tubular damage. Antioxidants like melanin and quercetin can mitigate this damage (Alshammari et al., 2023). Khan et al. found that GNPs induced acute-phase expression of pro-inflammatory cytokines in the renal cortex and medulla of rats, with a stronger response in the medulla (Khan et al., 2017). Shrivastava et al. confirmed that oxidative stress is a primary mechanism underlying the hepato- and nephrotoxicity induced by silver and gold nanoparticles (Shrivastava et al., 2016). In autophagy and apoptosis, Zhao et al. discovered that in normal HK-2 cells, AuNPs induced protective autophagy by inhibiting the Akt/mTOR pathway, whereas in cancerous cells, they induced apoptosis by upregulating p38 activity, revealing differential cellular responses to AuNPs based on cell type (Zhao et al., 2020). Ma et al. demonstrated for the first time that AuNPs can induce size-dependent Golgi fragmentation, leading to abnormal protein processing and reduced cell adhesion, unveiling a novel mechanism of nanoparticle toxicity (Ma et al., 2019). Samhadaneh et al. found that gold nanourchins compromise endoplasmic reticulum, redox, protein, and RNA homeostasis by activating the unfolded protein response and promoting RNA oxidation (Samhadaneh et al., 2019).

Under specific pathological conditions, the toxicity profile of AuNPs can be significantly altered. Under hypoxic conditions, Ding et al. showed that renal tubular epithelial cell uptake of GNPs increased significantly, leading to ROS production, reduced mitochondrial membrane potential, and increased apoptosis and autophagic cell death, whereas autophagy induced by GNPs under normoxic conditions promoted cell survival (Ding et al., 2014). In CKD models, Zhao et al., using an adriamycin-induced nephropathy mouse model, found that under hypoxic conditions, GNPs entering renal tubular epithelial cells and macrophages increased significantly, inducing excessive autophagy and inflammasome activation, potentially accelerating tubulointerstitial fibrosis (Zhao et al., 2021). In states of renal impairment, Ahrari et al. discovered that in an AKI mouse model, tubular injury significantly reduced glomerular filtration, leading to increased blood retention and renal accumulation of AuNPs. The blood retention of AuNPs correlated strongly with the urinary tubular injury biomarker KIM-1, suggesting that AuNPs could serve as a highly sensitive exogenous blood marker for tubular injury (Ahrari et al., 2025). Ning et al. found that in rats with severely impaired renal function, AuNP transport in the medulla was significantly slowed. In mildly injured kidneys, their transport correlated strongly with the degree of tubular injury rather than with conventional markers BUN and creatinine, emphasizing the need for caution when using renally-clearable nanomedicines in patients with compromised renal function (Ning et al., 2024).

Summary and future perspectives

In conclusion, gold nanomaterials, leveraging their tunable physicochemical properties and multifunctionality, occupy a central position in theranostic research for kidney diseases. Precise control of size (<5.5 nm) (Zhou et al., 2011; Zhang et al., 2014) and surface chemistry (Ning et al., 2017; Huang Y. et al., 2024) to achieve efficient renal clearance is a key strategy for mitigating long-term toxicity risks (Naz et al., 2016; Zhang et al., 2012). Diagnostically, AuNP-based CT (Au et al., 2013; Kim et al., 2007), SERS (Espinosa et al., 2025; Espinosa-Garavito et al., 2024), and fluorescence imaging (Yu et al., 2016; Zhao et al., 2024) techniques have significantly enhanced the sensitivity and specificity of early kidney disease detection. Therapeutically, AuNPs serve as drug/gene carriers (Peng et al., 2019a; Fang et al., 2022), photothermal/photodynamic agents (Al-Barram, 2021; Yuan et al., 2025), and direct antioxidant/anti-inflammatory agents (Saleh et al., 2022; Peres et al., 2023), offering novel therapeutic paradigms for various kidney diseases.

Nevertheless, several challenges must be addressed on the path from laboratory research to clinical translation. First, although numerous studies have confirmed that AuNP nephrotoxicity is size-, dose-, and surface-dependent (Abdelhalim and Jarrar, 2011a; Abdelrahman et al., 2023), the comparability across studies is often poor, highlighting the urgent need for standardized biosafety evaluation protocols (Garrigós et al., 2024; Zhu et al., 2021). Second, the long-term fate of nanoparticles in vivo, particularly the complex interactions within the “liver-kidney axis” (Qi et al., 2024) and the mechanisms of protein corona formation (Dubaj et al., 2022), require further in-depth investigation. Additionally, achieving the optimal balance between enhanced renal targeting efficiency (Fang et al., 2022; Song et al., 2025) and ensuring rapid clearance (Zhu et al., 2022; Liu et al., 2013) remains a core challenge in designing next-generation renal nanomedicines. Optimizing targeting ligand density has been identified as a critical regulatory parameter (Song et al., 2025).

Future research should focus on: 1) Developing “smart” AuNPs responsive to the disease microenvironment (e.g., pH, enzymes, ROS) for on-demand theranostics (Huang et al., 2025b; Zhao et al., 2024; Lai et al., 2020); 2) Exploring their potential in personalized precision medicine by integrating multi-omics technologies (e.g., metabolomics (Arendowski et al., 2020; Arendowski et al., 2021), genomics); 3) Utilizing more clinically relevant disease models (e.g., non-human primates (Xu et al., 2018)) to evaluate efficacy and safety; 4) Employing advanced imaging techniques (e.g., PET (Chen F. et al., 2016), two-photon microscopy (Morales-Dalmau et al., 2019)) to monitor nanoparticle fate in vivo in real-time. With a deepening understanding of nano-bio interface interactions (Wang and Liu, 2018), gold nanomaterials hold promise to overcome clinical translation barriers and become a standard tool in the armamentarium for diagnosing and treating kidney diseases.

Beyond the scientific hurdles, the clinical translation of AuNP based theranostics for kidney disease faces substantial practical and regulatory barriers. First, the scalable and reproducible manufacturing of AuNPs with tightly controlled physicochemical properties (size distribution <10% CV, consistent ligand density, endotoxin free) under Good Manufacturing Practice (GMP) conditions remains a non trivial engineering challenge. Sterilization presents another obstacle; conventional autoclaving or gamma irradiation can induce aggregation or ligand desorption, necessitating alternative strategies such as aseptic processing or sterile filtration, the latter of which is only feasible for ultrasmall AuNPs. Second, the regulatory pathway for AuNP products is ambiguous. Will a renally clearable AuNP intended as a CT contrast agent be regulated as a drug or a device? Will a theranostic nanoparticle that combines imaging and therapeutic functions require dual track approval? These questions remain largely unanswered by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), creating uncertainty for developers. Finally, the lack of standardized, validated in vitro and in vivo models for predicting human nephrotoxicity and clearance kinetics represents a critical knowledge gap. Concerted efforts from academia, industry, and regulatory bodies are required to establish a clear roadmap for the safe and effective translation of AuNP based technologies from bench to bedside.

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Footnotes

Edited by: Pradip Das, University of Southampton, United Kingdom

Reviewed by: Arindam Pramanik, Amity University, India

Dipranjan Laha, Washington University in St. Louis, United States