Gold and silver nanoparticles for safe and effective biomedical applications

Abstract

Metallic gold and silver nanoparticles have been extensively studied as nanoscale technologies for targeted gene and drug delivery agents. This narrative review incorporates the latest advances in the therapeutic and diagnostic potential of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) while also critically investigating their toxicity, safety concerns, and clinical translation. The therapeutic applications include antibacterial, antiviral, anti-inflammatory, anticancer, and dermatological applications. This review also provides a critical comparison between AuNPs and AgNPs in terms of their therapeutic potential and toxicological concerns. Epigenetic effects and clinical translation barriers are also compared. More importantly, AuNPs and AgNPs differ significantly in terms of their readiness to be translated clinically. As compared to AgNPs, greater biocompatibility and higher physicochemical stability are exhibited by AuNPs. On the other hand, AgNPs have been known to demonstrate higher cytotoxicity and antimicrobial potential but are at a higher risk of causing systemic toxicity and oxidative degradation. These therapeutic and diagnostic potentials are mainly due to surface plasmonic resonance, oxidative stress-associated cytotoxicity, surface functionalization, photothermal conversion, and nanoparticle-mediated cellular signaling pathway modulation. However, clinical translation of these metallic nanoparticles is still limited owing to toxicological concerns, biodistribution, and epigenetic or multigenerational issues. Therefore, incorporation of these metallic nanoparticles in clinical settings requires addressing systemic toxicity, controlled biodistribution, chronic toxicity, and standardization issues.

Introduction

Metallic nanoparticles have gained significant attention due to their unique physicochemical characteristics and are now being extensively studied in the field of biomedical sciences [1]. Due to their nanoscale size, adjustable optical properties, and customizable surfaces, these nanoparticles are now being used in gene delivery, biosensing, and target-specific drug delivery [1]. Over the years, metallic nanoparticles like those synthesized using gold and silver have been extensively used in the diagnosis and treatment of various cancers, viral diseases, microbial infections, and inflammatory conditions [2–5].

Nanomaterials have been known to possess unique physicochemical properties arising from a high surface-to-volume ratio, quantum effects, and tunable optical, electronic, and catalytic properties [6, 7]. Sized between 1 and 100 nm, these nanoparticles demonstrate optimized drug delivery, enhanced cellular uptake, and novel optical features, making them highly useful for biomedical applications [6, 7]. The nanosize of these particles causes them to interact with biomolecules, cellular membranes, and organelles, which affects biodistribution, cellular uptake, and their therapeutic activity [8]. Additionally, these nanoparticles have also shown potential in drug delivery and non-invasive imaging [9]. Key factors for regulatory clearance include following good manufacturing practices (GMP)Even though these nanoparticles show potential for biomedical applications, their clinical translation requires regulatory norms and standard practice guidelines [10, 11]. Key requirements for successful clinical translation include compliance with Good Manufacturing Practice (GMP), in vivo biodistribution, product reproducibility, long-term safety evaluation, manufacturing consistency, physicochemical stability and characterization (including colloidal stability, morphology, particle size, surface charge, and surface chemistry), sterility, and endotoxin testing [11–13]. Additionally, standardized physicochemical characterization is imperative for successfully translating these NPs clinically. A comprehensive evaluation of important parameters including dissolution, surface chemistry, particle size, morphology, surface charge (zeta potential), colloidal stability, and aggregation behavior is required. This is because these parameters directly regulate batch-to-batch consistency, biodistribution, cellular uptake, therapeutic efficacy, reproducibility, and toxicity. Standardized characterization also eases comparison across studies and may improve the reproducibility of clinical and preclinical findings [6, 7, 11–13].

While many reviews on AuNPs and AgNPs exist, their clinical translation still remains unclear owing to conflicting reports on toxicity, clinical readiness, underlying mechanisms, and AuNP versus AgNP comparison. Therefore, this review highlights recent advances in AuNP and AgNP research, with particular focus on their therapeutic and diagnostic potential, toxicity concerns, epigenetic considerations, regulatory concerns, and clinical translation barriers. The previously published reviews have mainly focused on either the diagnostics or therapeutic potential of AuNPs and AgNPs, whereas this narrative review provides an integrative framework for comparison between AuNPs and AgNPs. It mainly focuses on their ability to diagnose, translational challenges, toxicity, physicochemical properties, regulatory considerations, epigenetic impacts, and overall readiness to be translated clinically.

Methodology

Databases explored: For this narrative review, a structured literature search was performed using PubMed, Scopus, and Web of Science, supplemented by targeted search strategies in Google Scholar, to find very recent, published papers relevant to the scope of the review. The literature review consisted of publications from January 2010 to November 2025, which discuss the diagnostic, therapeutic, dermatological, and anti-inflammatory properties and toxicological effects of AuNPs and AgNPs. Search term combinations involve “gold nanoparticles,” “silver nanoparticles,” “nanomedicine,” “diagnostic,” “biosensor,” “lateral flow assay,” “SERS,” “photoacoustic imaging,” “drug delivery,” “photothermal therapy,” “photodynamic therapy,” “antiviral,” “antibacterial,” “dermatology,” “anti-inflammatory,” “toxicity,” “nanotoxicology,” and “epigenetic.” Some examples of boolean search strategies include (“gold nanoparticles” OR “AuNPs”) AND (“diagnostic” OR “biosensor” OR “lateral flow assay” OR “SERS” OR “photoacoustic imaging”), (“gold nanoparticles” OR “AuNPs”) AND (“drug delivery” OR “photothermal therapy” OR “photodynamic therapy”), and (“silver nanoparticles” OR “AgNPs”) AND (“antibacterial” OR “antiviral” OR “anti-inflammatory” OR “toxicity” OR “epigenetic”) and so on. These boolean search strategies were used across key databases. The eligibility criteria for literature review include original research articles, reviews, and meta-analyses written in English language that focus on biomedical or translational applications of AuNPs and AgNPs. Studies that provided mechanistic insight, in vivo validation, or clinically relevant data were given priority, along with review papers providing detailed insights on cross-domain research (for instance, diagnostics, oncology, and toxicology). Greater weight was provided to peer-reviewed literature with rigorous experimental controls, comprehensive physicochemical profiling, and outcomes of biological or clinical relevance. Conference abstracts, non‑peer‑reviewed preprints, and study reports that did not provide sufficient methodological information were not given priority as primary evidence, although they were sometimes referred to identify emerging trends. Although the review is narrative rather than systematic in design, a structured approach for search and evidence selection was adopted to improve transparency, rigorous critical analysis, and reliablethematic patterns. The studies were then selected accordingly, and were critically evaluated for translational relevance, mechanistic depth, methodological rigor, and consistency across the reported evidence. Findings were synthesized qualitatively, with attention to those providing coverage of consensus, inconsistency, methodological heterogeneity, sources of risk of bias, and unresolved gaps across in vitro, in vivo, and clinical studies relevant to future translational development. While this study is not designed as a systematic review, a structured approach for search and evidence selection was adopted to improve transparency, rigorous critical analysis, and reliable thematic patterns. Based on the selected literature, the use of AuNPs and AgNPs in diagnostics is discussed first, followed by their uses in therapeutics.

Diagnostic uses of gold and silver nanoparticles

Nanotechnology has reshaped biomedical research, and AuNPs and AgNPs represent two of the most analyzed nanomaterials concerning diagnostics and therapy. These nanoparticles have some unique chemical, electronic, and optical properties that can be manipulated very precisely by changing their dimensions, shape, composition, and surface chemistry, allowing for their use in biosensing platforms, imaging systems, targeted drug-delivery vehicles, and therapeutic modalities [14]. Prominent physicochemical features such as localized surface plasmon resonance (LSPR) and surface-enhanced Raman scattering (SERS) provide the basis for their enhanced sensitivity in analytic detection platforms, which also supports their increasing use in point-of-care imaging and biosensing platforms [2, 15]. However, the translation of these NPs into clinical use is still limited due to factors like instability, interference from biological fluids including protein corona formation, lack of standardization, and inconsistent reproducibility of signals [2]. It is also worth noting that AuNPs and AgNPs cannot be used interchangeably for diagnostic purposes. AuNPs are preferred more for biosensing and clinical imaging, as they are more biocompatible, offer higher stability, and their surfaces can be modified easily. Parallelly, AgNPs have been known to demonstrate higher amplification of SERS signals while simultaneously increasing plasmonic enhancement. However, AgNPs are susceptible to oxidation, degradation of signals, and release of ions at optimal conditions [2, 15–18].

AuNPs have become central in the modern development of diagnostic assays because of their biocompatibility, chemical stability, and easy surface modification. Due to their intense, tunable LSPR, measurable spectral shifts from tiny changes in size, shape, or aggregation are produced, and these spectral shifts can easily be exploited in colorimetric assays for the detection of nucleic acids, proteins, and pathogens [19]. The AuNP-based lateral flow assay (LFA) uses the characteristic red color of colloidal gold to provide fast point-of-care results that are easily interpreted, as is done in pregnancy tests and more recently in rapid tests against infectious diseases like COVID-19 [20].

Functionalization of AuNPs with specific ligands extends their application in plasmonic biosensors, whereby molecular binding events induce LSPR peak shifts, thus enabling sensitive, label-free detection of analytes [15]. AuNPs can be incorporated into SERS-active nanostructures to enhance local electromagnetic fields and, accordingly, enable the detection of molecules at extremely low concentrations, including single-molecule sensitivity, which is useful for early disease diagnosis [16]. Even though single-molecule sensitivity is achievable under tightly controlled lab settings, clinical translation still remains limited. This is due to signal instability, inconsistent generation of hotspots, and background interference from the sample matrix [15, 18, 21]. While AuNP-enhanced SERS systems may prove to be much more sensitive than standard colorimetric tests in lab conditions, their clinical translation is still limited due to issues like manufacturing standardization and consistent large-scale reproducibility [15, 16, 21]. However, it is worth noting that the conjugation of AuNPs with antibodies, aptamers, or DNA probes enhances diagnostic specificity and widens the applicability of the platforms [3].

AgNPs have been known to demonstrate stronger plasmonic enhancement properties, such as superior refractive index sensitivity and higher scattering cross-sections as compared to AuNPs, specifically with respect to SERS applications, although relatively lower chemical stability and biocompatibility limit practical use [2, 17, 18]. Enhanced optical responses of AgNPs have been greatly utilized in SERS biosensing, where substrates of AgNPs amplify Raman signals in the detection of molecular fingerprints with increased sensitivity and specificity [17]. Nevertheless, it is worth noting that long-term performance and signal reproducibility can be adversely affected by issues like oxidation, batch-to-batch variations, and physiological environment instabilities [17, 18].

AgNPs have also found application in LFAs, especially in their multiplexed formats, whereby size- and shape-dependent optical properties enable the detection of multiple analytes within a single test [22]. Synthesis advancements yielded silver nanostructures of specific morphologies—nanocubes, nanoprisms, and triangular platelets—offering tunable plasmonic properties and increased performance in biosensing applications. Stability and potential cytotoxicity are still concerns, and hybrid gold–silver formats are often used within diagnostic systems to take advantage of AgNPs’ enhanced sensitivity while ensuring the stability and biocompatibility conferred by AuNPs.

Among the most recognized and applied diagnostic platforms using the plasmonic properties of Au and Ag nanoparticles are lateral flow assays. LFAs most often rely on AuNPs conjugated with antibodies or other recognition elements that accumulate at the test line upon target binding to yield a visible red line without the need for specialized equipment [23]. Their simplicity, low cost, and rapid turnaround make them particularly useful in resource-limited settings, and the vital role played by point-of-care diagnostics in large-scale infectious disease screening over the course of the COVID-19 pandemic has underscored their clinical relevance [24]. Even with these benefits, conventional nanoparticle-based LFAs frequently demonstrate decreased sensitivity as compared to lab-based molecular assays, especially during the detection of samples with low analytes. Additionally, these LFAs may also demonstrate poor quantification and non-specific binding [23, 24]. Less frequently, AgNPs or Au–Ag hybrids are incorporated to enhance sensitivity and/or to offer expanded multiplexing capabilities [25].

SERS biosensors rely on the extraordinary capability of Au and Ag nanostructures to increase weak Raman signals by many orders of magnitude. Through the engineering of assemblies of nanoparticles that produce electromagnetic “hot spots,” SERS platforms may achieve ultra-low detection limits under controlled experimental conditions [18, 21]. Such systems have also found applications in the detection of a range of biomolecular targets, including nucleosides, microRNAs, and complex protein biomarkers relevant for early cancer and infectious disease diagnosis [26, 27]. Effective control of interparticle spacing and surface chemistry is crucial for SERS performance that could be reproducible and reliable for clinical use [21, 25]. Nevertheless, variations in substrate synthesis and inaccuracy of signal measurement are still barriers for clinical translation [15, 18, 21].

Thus, LSPR in plasmonic biosensors allows real-time monitoring of biomolecular interactions in a label-free way. When target analytes bind to nanoparticle-modified surfaces, it modifies the local refractive index and leads to measurable spectral shifts. Such sensors have succeeded in detecting DNA hybridization, antigen-antibody interactions, and early-stage cancer biomarkers using relatively enhanced sensitivity in a label-free method for liquid biopsy applications [24]. However, clinical diagnostic accuracy may be compromised due to issues like improper calibration, poor multiplexing, and changes caused in the refractive index due to complex biological matrices [15, 24].

In imaging, AuNPs have been prepared as contrast agents across modalities, including computed tomography (CT), photoacoustic imaging, and fluorescence imaging. With a high atomic number and strong X-ray absorption, they enhance CT contrast significantly compared with conventional iodine-based agents [27]. Due to lower ion-associated toxicity, better physicochemical stability, and more predictable biodistribution in the body, AuNPs are generally preferred more as compared to AgNPs [25, 26, 28]. This is primarily due to concerns regarding the systemic toxicity of Ag⁺ ions, due to which these ions are investigated mainly for antimicrobial functions. Additionally, as AuNPs demonstrate better biocompatibility and have been extensively researched clinically, they are preferred more over AgNPs. Further, this enables their use in near-infrared absorption for high-resolution photoacoustic imaging of tumors and vascular structures [26, 29]. With pronounced plasmonic responses, AgNPs have also been studied for imaging applications, yet stability and toxicity concerns have largely stood in the way of ultimate application, often shifting to gold–silver hybrids [21, 25].

Applications of liquid biopsy utilize AuNPs as both capture agents and signal amplifiers of the circulating biomarkers, such as tumor DNA, exosomes, and circulating tumor cells (CTCs) [30]. The large surface area offered by AuNPs supports dense functionalization with recognition molecules, therefore increasing target capture even in the presence of low concentrations of analytes [27]. Such a nanoparticle-based liquid biopsy platform enables noninvasive and sensitive diagnostics that may demonstrate a specificity that is highly desirable for early-stage diagnosis of cancer and precision medicine [24].

Collectively, AuNPs and AgNPs may be used for various diagnostic applications ranging from point-of-care assays to high-resolution imaging and ultra-sensitive biosensing, owing to their functionalizability, plasmonic properties, and chemical versatility. However, their clinical translation is still limited due to various concerns like batch-to-batch variability, protein corona formation, and signal reproducibility. Additionally, GMP-compliant production and regulatory approval are critical factors for clinical translation [12]. However, as AgNPs show greater chemical reactivity, long-term toxicity, and ion-associated cytotoxicity, they considerably encounter more difficulties during regulatory approval and safety assessment as compared to AuNPs [1, 11].

Table 1 summarizes the differences between Au- and Ag based nanoparticles in terms of clinical validation, sample type, and diagnostic characteristics. Fig. 1 summarizes the current research on the role of AuNPs and AgNPs in diagnosis and treatment in the fields of oncology, infectious diseases, and inflammatory conditions along with a comparative analysis that highlights mechanistic insights, translation issues, and safety concerns as well.

Table 1.

Comparative Evaluation of Differences between AuNP diagnostic platform and AgNP diagnostic platform

Diagnostic Platform	Nanoparticle	Diagnostic Application	Sample Type	Clinical Validation Status	Key Advantage	Reference
Colorimetric biosensor	AuNPs	Nucleic acid detection for disease diagnosis	Blood/Clinical samples	Experimental to translational	Rapid, simple, highly specific colorimetric detection	[19]
Plasmonic biosensor (LSPR)	AuNPs	Biomarker detection	Serum/Blood	Preclinical	High sensitivity, label-free detection	[16]
Aptamer-based biosensor	AuNPs	Cancer biomarker detection	Blood/Tissue	Preclinical	High specificity with molecular recognition	18]
Lateral Flow Assay (LFA)	AuNPs	Point-of-care disease diagnosis	Blood, saliva, nasal swab	Clinically established	Rapid, portable, inexpensive	[23]
SERS-based biosensor	AuNPs	Cancer and pathogen detection	Serum/Tissue	Experimental	Ultra-sensitive molecular fingerprinting	[15]
Silver nanoparticle optical biosensor	AgNPs	Optical and electrochemical biosensing	Clinical samples	Experimental	Strong plasmonic signal amplification	[17]
AgNP-assisted SERS sensor	AgNPs	Chemical and biomarker detection	Biological samples	Experimental	Excellent Raman signal enhancement	[21]
AgNP-enhanced biosensor	AgNPs	Point-of-care biosensing	Clinical samples	Experimental	High signal amplification with rapid detection	[17]
Nanoparticle-enabled diagnostic platforms	AuNPs & AgNPs	Multiplex biosensing and molecular diagnostics	Blood, serum, saliva	Emerging	Enhanced analytical sensitivity and multiplex capability	[24]

Fig. 1.

Application of gold and silver nanoparticles in therapeutics

Due to their widespread sales as point-of-care devices, cost-effectiveness, decreased turnaround time, and simplicity, among all the diagnostic platforms discussed earlier, LFAs based on AuNPs are currently at the forefront of being implemented clinically [23]. Additionally, owing to the difficulties in validating clinical readiness on a large scale, reproducibility, and standardization, plasmonic biosensors, which also involve SERS- and LSPR-based platforms, possess excellent analytical sensitivity [15–17, 21]. Similarly, even though approaches like liquid biopsy, photoacoustic imaging, and CT imaging have shown immense potential in being used for monitoring and diagnosis of disease, their clinical translation is still limited due to concerns like regulatory clearance and clinical validation [19, 24].

Anti-cancer applications of gold and silver nanoparticles`

The current conventional cancer therapies are now being paired with novel drugs and NPs to enhance drug delivery and efficacy while also reducing chemoresistance and systemic toxicity [4, 14]. Among metallic NPs, AgNPs and AuNPs have demonstrated higher potential owing to their ability for surface functionalization, unique cancer mechanisms, and therapeutic capability [4, 5]. However, their clinical translation is still limited due to various concerns like tumor heterogeneity, inconsistent biodistribution, chronic toxicity, and large-scale reproducibility [5, 11, 12]. There is an utmost need for effective drug administration protocols wherein the integration of pharmacological agents with natural or advanced molecules could play a pivotal role in minimizing the side effects of chemotherapy by reducing effective doses and inducing cellular self-protection against harmful agents [4].

AgNPs mainly demonstrate anticancer activity through oxidative stress-associated mechanisms, which involve excessive generation of reactive oxygen species (ROS), depolarization of the mitochondrial membrane, DNA damage, pro-apoptotic signaling pathway activation, and endoplasmic reticulum stress [31–33]. An increase in oxidative stress may promote the activation of caspase-3, while promoting the release of cytochrome-c, upregulation of BCL2-associated X (BAX), and mitochondrial bioenergetic disruption, ultimately causing the death of cancer cells [33]. Notably, AgNPs demonstrated selective cytotoxicity in certain cancer models. For example, in the SUM159 breast cancer cell line, AgNPs caused thiol oxidation, integrated stress response activation, and protein misfolding, whereas relatively lower cytotoxicity was observed in normal epithelial cells [33]. Nonetheless, ROS-associated cytotoxicity still remains largely dependent on surface chemistry, size of nanoparticles, exposure duration, and concentration, which causes cross-study heterogeneity [31, 33]. In addition to their direct anticancer effects, AgNPs have demonstrated novel applications in enhancing photodynamic therapy (PDT) [34]. The alkaloid berberine, a known antiproliferative and pro-apoptotic agent, has been tested on squamous carcinoma cells both as a standalone therapy and in combination with AgNPs. The results indicate that AgNPs may improve the anticancer properties demonstrated by berberine [35].

Owing to their target delivery, increased efficacy, and reduced multidrug resistance, AgNPs have been explored as nanocarriers for cancer therapy [4, 32]. ROS production, induction of cell cycle arrest, and apoptosis are some of the reported mechanisms that inhibit tumor growth [4, 33]. AgNPs loaded with carboplatin (AgNPs-Car) demonstrated targeted drug delivery to C6 glioma cells, with enhanced efficiency and reduced toxicity, which further suggests their applications as targeted drug delivery platforms [36].

Plant-derived biomolecules have also been used to synthesize biogenic AgNPs, as they may demonstrate enhanced efficacy, decreased synthesis-associated toxicity, and improved biocompatibility as compared to nanoparticles that are synthesized conventionally [35, 37]. However, standardization and clinical scalability are still limited due to variations in surface chemistry, phytochemical composition, and biodistribution [35, 38].

AuNPs have gathered attention as they have unique size and surface features that allow easy modifications with ligands to ensure specific targeting of tumor locations [5, 39, 40]. As compared to AgNPs, AuNPs generally demonstrate lower cytotoxicity. As a result, AuNPs are more preferred as imaging and drug delivery agents rather than providing intrinsic cytotoxicity [5, 31, 40]. AuNPs have beneficial characteristics and can be easily modified when supplemented with antibodies, peptides, or chemotherapy drugs. The recent advances in the field of nanotechnology have gathered attention in developing AuNP-based drug delivery systems to be translated clinically. Clinical translation, however, still requires addressing safety and regulatory concerns like toxicity, efficacy, bioavailability, and biocompatibility. Targeted drug delivery is one of the most important uses of AuNPs. Studies have established that the improved permeability and retention (EPR) effect may allow functionalized AuNPs to bypass healthy tissues and accumulate preferentially in tumor locations [5].

Furthermore, ligand-modified AuNPs can control drug release, which enhances the precision of therapeutic interference. The capacity to conjugate a wide type of ligands onto the surface of AuNPs, including peptides and antibodies, ensures that these nanoparticles can be customized for targeting a variety of cancer types, enhancing their applicability to various therapeutic strategies [31, 32]. In addition, for synthesizing AuNPs, involving physical and chemical methods, eco-friendly green synthesis approaches have gained significant attention. Green synthesis involves plant-derived biomolecules acting as reducing agents, offering a sustainable and biocompatible approach to nanoparticle production [26, 38].

The physiological properties of AuNPs mainly depend on the size and surface of the NPs. Induction of oxidative stress, apoptosis, and cellular uptake is strongly affected by the dimensions of the NPs [40, 41]. In an osteosarcoma cell line (MG63), enhanced ROS-associated apoptosis was observed as compared to smaller ones, which suggests that both mitochondrial dysfunction and cytotoxicity are strongly affected by the larger-sized AuNPs, rather than the smaller ones [41]. AuNPs may also cause disruption of the membrane potential in the mitochondria, activation of apoptosis pathways that are caspase-dependent, and enhanced lipid peroxidation [41, 42]. These size-dependent effects are further confirmed by SERS-based analyses [41]. However, excessive generation of ROS may also promote off-target toxicity and inflammatory responses, which suggests that optimizing surface chemistry, dose, and size of NPs are some of the factors that are necessary for clinical validation of NPs. This suggests that the optimization of nanoparticle size, dose, and surface chemistry remains critical for safe therapeutic translation [28, 43].

Overall, AuNPs mainly rely on photodynamic therapy, targeted drug delivery, and photothermal therapy to exert anticancer effects, whereas, on the other hand, AgNPs mainly provide anticancer effects through mechanisms like mitochondrial dysfunction and oxidative stress-mediated cytotoxicity [4–44]. However, it is worth noting that most of the evidence for the anticancer potential of AgNPs and AuNPs has been obtained from preclinical or in vitro models. Additionally, both tumor-selective delivery and anticancer potential are important for successful clinical translation. Although passive accumulation caused by EPR effect has been widely explored, its effectiveness is extremely varied among different tumor types. It is also considered to be less predictable in human-based tumors than in experimental animal models. In addition, therapeutic efficacy might be reduced owing to limited penetration of the tumor, quick clearance by the mononuclear phagocyte system, non-specific biodistribution, and heterogeneous vascular architecture [14, 39, 42, 45]. Therefore, extensive and large-scale clinical trials are required to mitigate concerns like systemic toxicity, regulatory concerns, efficacy, and GMP compliance before these NPs can be clinically translated for human use.

Antiviral effects

This subsection focuses on the role of AuNPs and AgNPs in the treatment of viral infections by summarizing the mechanisms of action and preclinical studies while highlighting the translational gaps. The antiviral effects of AgNPs have been extensively studied against viral infections across various species like plants, animals, and humans [26]. AgNPs are being evaluated as a potential treatment option against various pathogenic viruses of clinical relevance. This is because in preclinical and in vitro studies, AgNPs have been known to be effective against a wide variety of viruses, such as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis B virus (HBV), and monkeypox virus [26, 44, 46]. AgNPs may target various stages of the lifecycle of the virus by acting via multiple modes of action, including viral entry, replication, and attachment, although the exact mechanisms still need to be better understood and seem to be dependent on the study model, surface chemistry, and particle size of the nanoparticle used [26, 44, 46]. Even though the precise mechanisms through which AgNPs provide antiviral properties are still underexplored, existing research has demonstrated inactivation of the viral particles and preventing the virus from infecting host cells as two mechanisms for providing an antiviral effect. The enhanced surface area of the AgNPs might not allow the virus to bind to host cell receptors by increasing the interaction between AgNPs and the viral particle [26]. This is followed by the binding of AgNPs to viral particles, which might not only inhibit the entry of the viral particles but may also interfere with the other infection stages, like viral genome release inside the host [26, 44]. Additionally, AgNPs may also cause inhibition of viral nucleocapsids inside the infected cells and therefore might also disrupt essential metabolic pathways like protein synthesis, thereby inhibiting viral genome replication [26]. However, these mechanisms still need to be studied further to be clinically translated and validated. According to a study by [26], spherical-shaped AgNPs inhibited the adenovirus type 3 (Ad3) virus by causing viral structure disruption and viral DNA damage. These spherical-shaped AgNPs were synthesized through a chemical redox method and used tannic acid as a reducing agent. This led to a significant decrease in fluorescence intensity in Hela cells infected with Ad3 virus, thereby indicating the potential of AgNPs to impart antiviral properties. Various sources like plants, fungi, algae, and bacteria were explored to green-synthesize AgNPs with antiviral properties. A study by [44] demonstrated that AgNPs synthesized using fungi showed significant antiviral potential against human parainfluenza virus type 3 (HPIV-3), herpes simplex virus types 1 (HSV-1), and herpes simplex virus types 2 (HSV-2). Furthermore, pupicidal and larvicidal properties were observed against mosquito vectors causing malaria, dengue, Zika, and chikungunya due to the effect of green-synthesised AgNPs. These AgNPs were synthesized from plant extracts of Pedalium murex, Cleistanthus collinus, and Artemisia vulgaris, thereby providing environmentally friendly solutions to prevent vector-borne diseases [47]. By this, it can be concluded that in preclinical studies, AgNPs have demonstrated potential in treating viral infections and disease vector control either directly by viral particle disruption or indirectly by virus replication inhibition. However, clinical translation of these AgNPs for viral disease treatment still requires addressing issues like inconsistent biodistribution, systemic toxicity, and insufficient in vivo testing [11, 26, 44].

AuNPs have also demonstrated immense potential in fighting a wide range of viral infections, including respiratory viruses, HIV, HSV, and influenza. However, just like AgNPs, the evidence available is mostly from in vitro studies, and that from in vivo investigations is still insufficient [8, 26, 48]. According to a study conducted by [49], non-functionalized AuNPs showed significant antiviral properties against HSV-1 in Vero cells. This was evident by the significant decrease in the cytopathic effect of HSV-1 in Vero cells in a time- and dose-dependent manner. Furthermore, AuNPs also demonstrated significant activity against the influenza A virus [46], which indicates that AuNPs could be used to treat diseases caused by enveloped RNA viruses. These RNA viruses depend on host cell machinery for replication and survival, which gets disrupted by AuNPs, particularly disruption of subcellular structures like lysosomes and the cytoskeleton. Additionally, AuNPs were also found to have high antiviral potential against lentivirus and human coronavirus OC43 [48].

AuNPs, when functionalized with various functional groups, are also found to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to a study by [50], AuNPs were functionalized using a peptide designed from the amino acids found in angiotensin-converting enzyme 2 (ACE2). These functionalized AuNPs were found to interact with the receptor binding domain of SARS-CoV-2, which suggests AuNPs can be considered a potential antiviral candidate for treating COVID [50]. Pseudomonas mendocina CH50 has also been employed to sustainably produce AuNPs, which, when combined with polyhydroxyalkanoate (PHA), were found to cause a significant increase in antibacterial and antiviral activity, as evidenced by a 75% decrease in viral infectivity of the SARS-CoV-2 pseudotype [51].

Therefore, it may be concluded that through various mechanisms like viral entry inhibition, ROS, and cellular process disruption, promising antiviral properties are exhibited by AuNPs. However, most findings are obtained from preclinical studies, and clinical translation still requires addressing long-term safety concerns and inconsistent biodistribution [8, 11, 48]. Even though antiviral activity is exhibited by both AgNPs and AuNPs, both are being used for entirely different purposes. AuNPs are being used mainly as vaccine carriers and targeted delivery platforms, whereas AgNPs interact directly with the virus particles to demonstrate virucidal effects for which these NPs inhibit replication, entry, and attachment of the virus [47–50].

Antibacterial effects of AuNPs and AgNPs

This subsection critically compares AuNPs and AgNPs in terms of their therapeutic potential, translational limitations, and antibacterial mechanisms while focusing on the efficiency with which the bacteria are targeted, physicochemical properties, clinical translation, and toxicity concerns. As compared to AuNPs, AgNPs have the potential to be used as broad-spectrum antimicrobial agents for both Gram-positive and Gram-negative bacterial strains. These strains may also include multidrug-resistant strains and act primarily through sustained release of Ag⁺ ions. However, the clinical translation of AgNPs may be limited due to concerns like stability, greater cytotoxicity, and oxidative stress-related concerns [28, 52–54]. AgNPs may act in numerous ways, like causing cell membrane disruption, generating oxidative stress, disrupting respiratory chain enzymes, releasing intracellular Ag⁺ ions, and adversely affecting DNA replication [52, 54, 55]. When AgNPs are supplemented with potent antimicrobial agents like antibiotics or other organic compounds, a higher efficiency is observed against pathogenic microbes like Escherichia coli and Staphylococcus aureus [52].

Additionally, AgNPs synthesized using natural sources also possess the potential to fight broad-spectrum bacterial infections partly due to the synergistic effect of the phytocompounds and AgNPs [35, 38, 56]. Examples include potent antibacterial activity shown by Carduus crispus-synthesized AgNPs against Escherichia coli and Micrococcus luteus and Artemisia vulgaris leaf extract-synthesized AgNPs against various pathogens like Klebsiella pneumoniae, E. coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae by influencing bacterial enzyme metabolism and ribosome activity [57].

The widespread antimicrobial properties of AgNPs have been used extensively in dentistry to prevent and treat bacterial infections in teeth [58]. Significant antibacterial and antibiofilm formation activities are found in AgNPs synthesized using green synthesis methods. Extracts formed from plants such as Bridelia retusa, Semecarpus anacardium, and Glochidion lanceolarium have also shown significant antibacterial activity against various human pathogenic bacteria like Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli [52, 59]. Furthermore, AgNPs supplemented with ethanolic extract of Rosa indica petal have also shown significant antibacterial properties. This potency was observed against Gram-positive bacteria like Streptococcus mutans and Enterococcus faecalis, as well as Gram-negative bacteria like E. coli and Klebsiella pneumoniae. These observations were based on minimum inhibitory concentration (MIC) assays [60]. Green-synthesized AgNPs from Pandanus foetidus and Alangium salvifolium exhibited a crystalline structure with a spherical morphology, demonstrating antimicrobial activity, particularly against Shigella boydii [61]. However, it is important to note that these findings are only limited to in vitro minimal inhibitory concentration (MIC)-based studies, and factors like differences in the size of NPs, method of synthesis, surface charge, and the formation of protein corona need to be standardized for higher reproducibility and clinical validation [11, 28, 62].

Due to an increase in antibiotic resistance, alternative therapies to fight bacterial infections have become the need of the hour. AuNPs are one such alternative owing to their distinctive antibacterial properties. AuNPs are known to act in numerous ways and are effective against Gram-positive, Gram-negative, and multi-drug-resistant bacterial strains as well. AuNPs primarily act by physically interacting with the bacterial cell membrane, thereby causing cell membrane disruption due to an increase in the membrane permeability [63]. Small-sized AuNPs may be able to penetrate bacterial envelopes with higher efficacy, which might enable the NPs to interact with the proteins and nucleic acids involved in metabolic regulation and replication [39, 63]. Some other modes of action of AuNPs include causing DNA damage, which adversely affects replication and survival. Additionally, the generation of oxidative stress due to an increase in the concentration of ROS is also a common mechanism to kill or prevent bacterial growth. The mode of action by ROS generation is especially effective against multi-drug-resistant strains. ROS acts by disrupting bacterial metabolism and membrane oxidation, which causes the bacterial cells to die [63].

As compared to AgNPs, AuNPs generally demonstrate decreased antimicrobial activity but may show improved surface functionalization capacity and biocompatibility. This suggests that AuNPs may be considered as potential candidates for photothermal and targeted carriers for antimicrobial properties [28, 64]. The antibacterial properties of Au-derived nanostructures are known to be strongly affected by physicochemical features like size, surface charge, morphology, and functionalization chemistry, all of which may be involved in regulating cellular uptake, photothermal conversion efficiency, and bacterial adhesion [2, 64]. Based on shape, some types of nanoformulations include Au-nanoparticles (AuNPs), Au-nanoclusters (AuNCs), Au-nanorods (AuNRs), Au-nanobipyramids (AuNBPs), and Au-nanostars (AuNSs). AuNPs are the most common gold nanoformulations studied and are known to demonstrate size-dependent antibacterial effects. Smaller AuNPs cause membrane disruption and ROS generation, as these can easily pass through the bacterial membranes [56]. AuNCs also follow similar modes of action as that of AuNPs, as the nanoclusters are minute-sized particles that can easily penetrate the bacterial membranes and internalize inside the bacteria [56]. AuNRs, AuNBPs, and AuNSs provide antibacterial properties by using their unique shapes and surface areas, which affect how these nanoformulations interact with the bacterial cell membranes [63].

AuNPs also help in indirectly treating bacterial infections using photothermal therapy (PTT) and photodynamic therapy (PDT). In PTT, AuNPs help convert light into heat, which kills bacterial cells, whereas in PDT, AuNPs activate light, which kills bacteria due to the generation of ROS. In preclinical studies. AuNP-based PDT and PTT systems were able to demonstrate increased activity against biofilms and multidrug-resistant bacteria mainly through ROS-mediated oxidation of the bacterial membranes and localized hyperthermia. However, clinical translation still requires addressing concerns like biodistribution inconsistency, optimization of the depth of laser penetration, in vivo pharmacokinetics, and long-term safety [25, 34, 65]. Surface functionalization is performed by modifying the surface with specific ligands or other molecules; AuNPs show a significant increase in antibacterial potential while also preventing toxicity to normal cells. Due to functionalization, AuNPs can act more effectively against multi-drug-resistant bacteria such as Staphylococcus aureus and Escherichia coli to perform passive diffusion and surface adhesion to disrupt bacterial membranes [65].

Furthermore, certain functionalized AuNP systems were able to suppress the multidrug resistance development over numerous generations. This suppression was due to synergistic mechanisms such as physical membrane disruption and oxidative damage, which makes it harder for the bacteria to be able to adapt [66]. AgNPs generally demonstrate direct, stronger antibacterial activity due to ROS-associated damage and release of Ag⁺ ions. On the other hand, rather than acting as a direct antibacterial agent, AuNPs offer photothermal properties, better surface tunability, and biocompatibility. However, concerns like instability, toxicity, regulatory challenges, inconsistent pharmacokinetics, and protein corona formation need to be addressed properly before both AuNPs and AgNPs can be translated clinically [10–13, 28, 62]. When compared with AuNPs, AgNPs mostly demonstrate a stronger antibacterial property owing to inhibition of biofilm generation, increase in oxidative stress, membrane disruption, and release of Ag⁺ ions. On the other hand, AuNPs are mainly employed as drug delivery agents to increase antimicrobial efficiency [51–61].

However, it is worth noting that even though AgNPs demonstrate broad-spectrum antibacterial potential, they should be used judiciously and cautiously, as long-term exposure may lead to NP tolerance or microbial adaptation [52, 55, 63]. Additionally, there is also a need to further investigate the potential effects of AgNPs once they are released into the environment and their effect on beneficial microbes and the host microbiome [20, 67]. This suggests that there is a dire need for optimization of dosage, clinical applications, and nanoparticle formulation to increase therapeutic efficiency while suppressing adverse biological or environmental effects [52, 67].

Dermatological effects of gold and silver nanoparticles

This subsection focuses on the dermatological applications of AuNPs and AgNPs by summarizing the mechanisms of action and preclinical studies while highlighting the translational gaps. Current research on the use of AgNPs and AuNPs has underlined their potential for dermatological applications. AuNPs have been extensively studied for treating acne vulgaris. These nanoformulations may cause an increase in the phototherapy efficiency by targeting the sebaceous glands or by enabling local drug release [68]. Additionally, AuNPs have also shown potential in creating topical formulations for dermatological uses owing to their distinctive optical properties, which may further play a role in enhancing phototherapy and transdermal applications [69]. Similarly, AgNPs have been known to demonstrate broad-spectrum antimicrobial properties and anti-inflammatory properties, which have been used for treating acne, dandruff, and different wound care stages by preventing microbial infections and inducing tissue repair [70].

Nanoformulations may also help in improving the targeted delivery and topical application of dermatological agents [71]. Also, their incorporation into sunscreen formulations may improve ultraviolet (UV) protection, as light scatters effectively without the white residue usually left by conventional filters [72]. However, despite this fact, long-term safety, potential toxicity, and systemic effects are considered serious concerns, and it is important to continue performing research to complete the refinement of such formulations to establish consumer safety [69]. Therefore, therapeutic outcomes that target specific skin conditions while also employing strict safety testing have become the need of the hour. These advances are mainly caused due to the blending of metallic NPs into cutaneous formulations.

Current treatment options for chronic skin conditions like psoriasis, ichthyosis, and atopic dermatitis are mostly ineffective due to limitations in drug delivery and penetration. One way to overcome these limitations is by using nanoformulations owing to better bioavailability and controlled release of bioactives. Due to these features, the dermatological interventions are now increasingly efficient and are easy to apply. Rather than the oral route of administration, topical routes are usually preferred owing to fewer side effects due to limited exposure and precise therapeutic targets. These topical applications, when supplemented with nanoformulations, may provide better delivery and therefore may be translated clinically. However, there is still a need for extensive research on safety concerns, drug formulation stability, and drug tolerance. Cosmetic applications, targeted drug delivery, and skin regeneration are some of the primary uses for which AuNPs are being studied primarily. On the other hand, owing to their broad-spectrum antimicrobial and anti-inflammatory activities, AgNPs are being widely used in topical formulations and wound dressings [63–68]. Although these NPs have demonstrated promising applications in dermatology, it is important to ensure that long-term exposure, local irritation, skin penetration, systemic absorption, and formulation stability are optimal [71, 72]. Additionally, extensive long-term clinical trials and safety studies are required to ensure these NPs are ready for clinical translation to be used as cosmetic and dermatological products [68, 69].

Anti-inflammatory effects of AuNPs and AgNPs

This subsection focuses on the anti-inflammatory effects of AuNPs and AgNPs by summarizing the mechanisms of action and preclinical studies while highlighting the translational gaps. Present-day research has increasingly outlined the anti-inflammatory potential of metallic nanoparticles, mainly those made using silver and gold through green synthesis or bio-based techniques. The major focus of these studies is to improve the biocompatibility and efficacy of these nanoparticles. Different experimental models have been studied to demonstrate the significantly high anti-inflammatory potential of green synthesized AgNPs [64]. For example, a study by [73] showed a significant reduction in edema, levels of high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) when adjuvant-induced arthritis models of rats were treated with curcumin-coated AgNPs, therefore suggesting that AgNPs could reduce arthritic inflammation. Another study by Abdelhafez et al. (2020) reported significant terpenoid-mediated inhibition in levels of cyclooxygenase-2 (COX-2) in AgNPs synthesized from soft coral Nephthea sp. A study by [74] has demonstrated the dual-acting potential of AgNPs synthesized using Cotyledon orbiculata at low concentrations, demonstrating concentration-dependent antimicrobial and anti-inflammatory action against Pseudomonas aeruginosa. Additionally, a significant suppression of pro-inflammatory cytokines like interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 was observed in macrophages stimulated by lipopolysaccharides (LPS). Furthermore, it was observed that when AgNPs were synthesized using Ocimum tenuiflorum and Stevia rebaudiana extracts, a significant increase was observed in antioxidant and anti-inflammatory potential as compared to conventional nanoparticles [75]. AgNPs may also promote the process of tissue repair by reducing the production of pro-inflammatory cytokines, which suggests their potential to be used as a therapy for various conditions like wound healing and arthritis [76]. AuNPs are also known to significantly inhibit the production of pro-inflammatory markers like TNF-α and IL-6, which play important roles in the progression of chronic diseases like coronary artery disease [77].

According to a study by [78], it was demonstrated that AuNPs affect dendritic cells and macrophages in a completely different manner, thereby increasing antigen presentation and regulating the secretion of cytokines as well. According to research conducted by [79], it was shown that treating periodontal disease with 45 nm-sized AuNPs led to a shift in macrophage type from a pro-inflammatory to an anti-inflammatory state. This shift in macrophage state helps in regenerating periodontal tissues by causing a significant increase in cellular differentiation of human periodontal ligament cells (hPDLCs). AuNPs are known for their ability to decrease oxidative stress and inflammation by reactive oxygen species (ROS) scavenging and inhibition of various inflammation signaling pathways. These pathways include Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT), Mitogen-Activated Protein Kinase (MAPK), and Nuclear Factor kappa-light-chain-enhancer of activated B Cells (NF-κB) [80]. However, the anti-inflammatory effects of AuNPs are mainly dependent on the in vivo biodistribution, nanoparticle size, surface chemistry, and concentration, due to which their clinical translation is still limited [80]. Overall, through mechanisms like modulation of ROS and pro-inflammatory cytokines’ suppression, AgNPs mainly demonstrate anti-inflammatory action, whereas AuNPs may provide improved biocompatibility, greater immunomodulatory control, and pathway-specific regulation as compared to AgNPs.

In brief, even though AgNPs and AuNPs exhibit comparable plasmonic functions and wide diagnostics and therapeutic applications, their biological mechanisms of action, physicochemical characteristics, and degree of clinical translation are extremely different. While both AuNPs and AgNPs have demonstrated significant potential to modulate anti-inflammatory pathways, greater biocompatibility is exhibited by AuNPs, whereas AgNPs exhibit anti-inflammatory properties, which are highly dependent on exposure duration, dosage, surface chemistry, and particle size [64, 69–72]. Although the anti-inflammatory potential of AuNPs and AgNPs has been demonstrated by numerous studies, it is worth noting that they demonstrate immunological effects that are context-dependent. However, depending on the model system used, exposure duration, concentration, coating, surface chemistry, and the size of NPs, pro-inflammatory responses have also been observed. These responses are due to immune cell activation and oxidative stress [53, 77, 78]. This suggests that it is imperative that a thorough optimization of dosage and nanoparticle design be done to ensure enhanced therapeutic efficacy and minimal adverse effects like unintended immune activation [81]. Table 2 provides a structured comparison of AuNPs versus AgNPs across these variables. Therefore, even though AuNPs and AgNPs have widespread biomedical applications, concerns regarding their safety and toxicity-associated effects, including long-term biocompatibility, organ accumulation, immunological responses, oxidative stress, and dose-dependent cytotoxicity are still critical and require extensive research as discussed in the following section.

Table 2.

Comparative Evaluation of Differences between AuNPs and AgNPs

Parameter	AuNPs	AgNPs	Translational Relevance	References
Physicochemical stability	High chemical stability with minimal ion release; resistant to oxidation	Oxidative dissolution releases Ag⁺ ions; stability depends on size and coating	Stability influences circulation, storage and regulatory approval	[1, 53]
Plasmonic functionality	Tunable LSPR suitable for imaging, SERS and photothermal therapy	Strong plasmonic activity but reduced long-term stability	AuNPs are more mature for clinical diagnostic platforms	[2, 16, 17]
Drug delivery	Efficient thiol functionalization enables targeted drug delivery	Drug carrier potential but Ag⁺ release may limit therapeutic safety	AuNPs demonstrate greater translational potential for drug delivery	[32, 39]
Anticancer mechanisms	Photothermal therapy, apoptosis induction and signalling modulation	ROS generation, DNA damage and mitochondrial dysfunction	Most evidence remains preclinical for both nanoparticle types	[33, 40]
Antimicrobial mechanisms	Limited intrinsic antimicrobial activity; improved after conjugation	Broad-spectrum antimicrobial activity through membrane disruption and Ag⁺ release	AgNPs are clinically used in wound dressings and antimicrobial coatings	[28, 53, 55]
Antiviral mechanisms	Inhibits viral attachment and intracellular trafficking	Disrupts viral envelope and inhibits viral replication	Clinical validation remains limited	[44, 46, 48]
Biodistribution	Mainly accumulates in liver and spleen	Accumulates in liver, spleen and kidneys with greater oxidative stress	Biodistribution influences long-term safety and clearance	[82, 83]
Immune modulation	Mild modulation of macrophage and dendritic-cell function	Greater cytokine release and inflammasome activation	Important determinant of immunotoxicity and therapeutic safety	[78, 81]
Epigenetic effects	Mild alterations in DNA methylation and gene regulation	DNMT1 downregulation, histone modification and oxidative DNA damage	May affect long-term safety and regulatory assessment	[84–86]
Clinical relevance	Advanced development for diagnostics, imaging and theranostics owing to favourable biocompatibility	Commercially established mainly for antimicrobial coatings and wound dressings; systemic applications require further safety evaluation	AuNPs currently show greater clinical readiness than AgNPs	[28]

Toxicity of gold nanoparticles

There has been a considerable amount of research that has reported the potential use of metallic nanoparticles in various medical applications. These include drug carriers, target-specific drug delivery, tumor detectors, and therapeutics. But experimental usages of AuNPs have possible medical hazards due to their surface-to-volume ratio, which enhances their catalytic properties and makes them highly reactive [7]. The AuNPs at the nanoscale level may exhibit different size-related properties, which vary greatly from their non-nano-scaled properties. At the nanoscale, AuNPs can easily cross the cellular membrane and interact with the intracellular components [87]. It is difficult to predict the potential risk of AuNPs inside the cell.

Cytotoxicity is driven by parameters such as the size of nanoparticles, surface chemistry, and surface charge. These help in determining the electrical double layer structure and van der Waals forces that mediate nanoparticle binding to the phospholipid bilayer [87]. Recent in vivo studies have unraveled the significant dependence of AuNP toxicity on the size of nanoparticles, functionalization of the surface, and surface chemistry. Toxicity studies in embryonic zebrafish demonstrated size- and charge-dependent effects; exposure to 1.3 nm N, N,N-trimethylammoniumethanethiol (TMAT)-functionalized AuNPs resulted in pronounced developmental toxicity, embryo lethality, and multiple morphological abnormalities—reduced eye size and hypopigmentation—which increased apoptotic death and disrupted the expression of transcription factors essential for ocular and pigmentation development [82]. 1.5 nm AuNPs functionalized with 2-mercaptoethanesulfonic acid (MES), TMAT, or 2-(2-(2-mercaptoethoxy) ethoxy) ethanol (MEE) were compared [88]. TMAT-AuNPs proved to be lethal, MES-AuNPs were found to be sublethally malformative, and MEE-AuNPs were found to be biologically inert; MES- and TMAT-AuNPs were associated with inflammatory responses, immune activation, and transport dysregulation, underlining the pivotal role of surface chemistry in molding both phenotypic and molecular outcomes. It was found by [89] that long-term exposure of AuNPs in Drosophila melanogaster induced strong phenotypic changes, which were transmitted to future progenies as well. Additionally, a study by [43] showed that 10 nm AuNPs were non-toxic when administered alone. However, when AuNPs were given synergistically with lipopolysaccharide (LPS), they worsened the acute liver injury in BALB/c mice. This suggests that the toxicity effect observed could be different in healthy people as compared to people with pre-existing conditions, which underscores the relevance of biological context and the relevance of dose during preclinical evaluations. By this, it can be concluded that even though AuNPs do not show any effect directly, they can aggravate pre-existing inflammatory conditions as shown when combined with LPS, thereby causing organ toxicity. Therefore, long-term profiling of toxicological effects, standardization of physicochemical characterization, and disease-relevant models for in vivo studies are required to obtain regulatory approvals for successful clinical translation (Fig. 2).

Fig. 2.

Factors and exposure conditions influencing the toxicity of AuNPs

Toxicity of silver nanoparticles

AgNPs have distinct properties that make them suitable for various applications, ranging from various day-to-day goods to the products of medical use. Despite having growing evidence for the adverse effects of AgNPs on health and the environment, there is scope to explore the harmful/toxic effects comprehensively.

Due to emerging physicochemical characteristics of AgNPs, it is needed to explore the effect of the size of nanoparticles, surface charge, and surface functionalization to determine optimal dosage and to understand its toxic effect with respect to biological or environmental context [53]. Recent reviews show that the smallest particles, particularly those below 10 nm, are more reactive, dissolve more readily to Ag⁺, and provoke stronger oxidative stress responses. Together, these factors drive greater cytotoxicity and genotoxicity than larger particles at the same mass concentration [53, 90]. Because AgNPs dissolve partially and release Ag⁺ ions, which are a major cause of AgNP-associated toxicity. Nonetheless, other characteristic features such as the size of particles, surface chemistry, and cellular internalization may also act as a cause of some of these toxic effects [53]. The shape of the nanoparticles, in addition to their surface planes and the extent of aggregation, also determines cellular uptake and distribution. Additionally, these factors also help in deciphering whether the toxicity is because of AgNPs or Ag⁺ ions [53]. Overall, the relatively greater toxicity of AgNPs as compared to AuNPs is primarily due to the release of Ag⁺ ions, which may increase the generation of reactive oxygen species (ROS), cause DNA genotoxicity and damage, promote mitochondrial dysfunction, and may also induce lysosomal accumulation following cellular internalization. In contrast, AuNPs generally exhibit greater chemical stability with minimal ion release, contributing to comparatively lower oxidative stress and improved biocompatibility under similar experimental conditions [40, 53, 91–93].

Various studies have demonstrated that surface charge has a higher potential in causing cytotoxicity and distribution as compared to protein corona effects. This is evident from the fact that AgNPs with a positive charge have a significantly higher potential to internalize and pile up in the lysosomes while causing extensive damage to the mitochondria. On the other hand, AgNPs with a negative charge demonstrate significantly decreased uptake, which corresponds to a lower toxic effect, observed in the most sensitive cell types as well [62]. The oxidative stress-associated effects were found to be strongly dependent on particle size, stabilizer, concentration, and exposure duration [90]. These insights are extended into complex media by environmental and agricultural studies that show pH, ionic strength, and organic ligands to control AgNP aggregation, dissolution, and sulfidation, which, in turn, modulate bioavailability and toxicity in plants and microbes due to effects on membrane integrity, oxidative injury, and interference with key metabolic processes [55, 67]. Industrial processes result in significant release of silver into the environment, with toxicity in aqueous media known to be caused mainly due to Ag⁺ ion dissolution from AgNPs rather than the AgNPs themselves [67]. In humans, exposure to soluble silver compounds has been linked to argyria and argyrosis (permanent bluish-gray discoloration of skin or eyes), as well as systemic toxicities, including hepatic and renal impairment; irritation of eyes, skin, respiratory tract, and gastrointestinal system, and hematological changes were also reported [67].

It is also crucial to note that AgNP-associated toxicity is also dependent on the route of administration, time of exposure, dosage, and model system studied. Although research into nanosilver toxicity is still in its preliminary stages, the available evidence indicates significant biological hazards. According to a study by [94], when BALB/c male mice were subjected to 35 injections of a daily dose of 10 nM AgNPs, these were found to have a glassy appearance, necrosis, and degeneration of hepatocytes. Additionally, these AgNPs were also known to cause apoptosis, hyperplasia of Kupffer cells, sinusoidal dilation, and significant changes in the ultrastructures of hepatocytes. AgNPs and silver nitrate were shown to affect the development and specification of endoderm and mesoderm layers while also affecting the generation and functioning of endoderm-derived hepatocytes [95]. Other studies have shown that nanosilver alters the proliferation and cytokine expression of peripheral blood mononuclear cells [81] and evokes serious toxic effects on the male reproductive system due to its distribution within testicular tissues across the blood-testis barrier, hence causing damage to sperm cells [96]. A study on rodents unfolds the effects of oral administration of AgNPs on hepatic toxicity, where histopathological changes have been reported, such as bile duct hyperplasia, necrosis, fibrosis, and pigment deposition, which were also observed [83]. Additionally, a study by [97] demonstrated that 72-hour exposure to AgNPs led to developmental toxicities in zebrafish models. This is evident by the significant reduction in hatching, abnormal phenotypes, and increased mortality due to increased ROS and lipid peroxidation, accompanied by significant mitochondrial damage. The safety and translational applicability of nanoparticles are based on multiple factors and their synergistic effects, such as composition, size, surface chemistry, dose, the route of exposure, and the biological model system used for evaluating the toxicity (Fig. 3). It is indicated that AgNPs have a narrow therapeutic window for the dosage range. Therefore, there is a need for application-based standardized dosage, long-term in vivo studies, and reproducible physicochemical features to prevent toxicological effects rather than only relying on isolated in vitro studies. Representative clinically approved, clinically investigated, and commercially available biomedical products based on AuNPs and AgNPs are summarized in Table 3 to provide an overview of their current translational status.

Fig. 3.

Factors and exposure conditions influencing AgNP Toxicity

It is also worth noting that in addition to toxicity, AuNPs and AgNPs are also known to cause epigenetic effects, which may or may not occur in successive generations, as discussed in the upcoming section. As demonstrated in Table 4, the toxicological effects shown by NPs are mainly dependent on the biological system, size, surface chemistry, charge, and dose of the NPs. Therefore, these findings underscore the need for standardization of physicochemical profiling in biological models relevant for clinical use.

Table 3.

A list of commercially available, clinically approved, clinically tested, or commercially used AuNP- and AgNP-based biomedical products

Sr. No.	Nanoparticle	Product / Platform	Biomedical application	Clinical / Commercial status	Remarks	References
1	AuNPs	Verigene® System (Luminex)	Molecular diagnostics for infectious diseases	Commercially available	AuNP-based nucleic acid detection platform used in clinical laboratories for rapid pathogen identification.	[19, 23, 24]
2	AuNPs	Gold nanoparticle-based Lateral Flow Assays (LFAs)	Point-of-care diagnostics	Commercially available	AuNPs function as colorimetric labels owing to excellent optical properties, rapid detection, low cost, and ease of use.	[2, 23, 24]
3	AuNPs	CYT-6091 (Aurimune®)	Targeted cancer therapy (TNF-α delivery)	Phase I clinical trial completed	PEGylated AuNP formulation designed to improve TNF-α delivery while reducing systemic toxicity.	[31, 39]
4	AuNPs	AuroLase® Therapy (Nanospectra Biosciences)	Photothermal cancer therapy	Clinical investigation	Silica–gold nanoshell platform activated by near-infrared laser for localized tumor ablation.	[31, 37]
5	AuNPs	Experimental AuNP imaging probes	CT imaging, photoacoustic imaging and biosensing	Preclinical to early translational stage	Promising imaging platforms requiring further clinical validation and regulatory approval.	[2, 3, 16]
6	AgNPs	Acticoat®	Burn wound management	Commercially available	Nanocrystalline silver dressing providing sustained antimicrobial activity.	[59]
7	AgNPs	Aquacel® Ag	Chronic wound care	Commercially available	Hydrofiber dressing containing ionic silver for infected and chronic wounds.	[59]
8	AgNPs	Silverlon®	Surgical and burn wound dressing	Commercially available	Silver-coated dressing widely used for infection prevention and wound healing.	[59]
9	AgNPs	AgNP-coated medical devices	Catheters, orthopedic implants and wound coatings	Commercially available	Silver coatings reduce microbial colonization and biofilm formation on medical devices.	[4, 40]
10	AgNPs	Experimental AgNP-based anticancer formulations	Drug delivery and cancer therapy	Preclinical	Promising anticancer efficacy; systemic clinical translation remains limited by toxicity and regulatory concerns.	[4, 32, 37]

Epigenetic effects of gold and silver nanoparticles

Epigenetic regulation may play an important role in both the toxicological effects and therapeutic potential of AgNPs and AuNPs. Recent evidence has increasingly focused on the ability of AgNPs and AuNPs to affect epigenetic regulation, an aspect with broad implications for toxicity and therapeutic applications. These epigenetic changes mainly involve gene regulation mediated by non-coding RNAs, DNA methylation, and histone modifications, while recent evidence also suggests that after AuNP and AgNP exposure, it is possible that these epigenetic changes could pass on from generation-to-generation. Out of AgNPs and AuNPs, the former is known to have stronger modulatory effects on epigenetic signatures. There are numerous pathways that cause these AgNP-associated epigenetic effects. Out of these, one highly affected pathway involves proteasomally degrading an enzyme known as DNA methyltransferase 1 (DNMT1). This enzyme is majorly responsible for ensuring that DNA methylation occurs during replication. This degradation could lead to hypomethylation of DNA in the global population. DNA hypomethylation is one of the major characteristics of dysregulation at the gene level [84]. This epigenetic dysregulation may change the gene expression of various genes associated with inflammation, apoptosis, cell cycle deregulation, and oxidative stress responses, hence influencing both NP-associated therapeutic potential and NP-associated toxicity. Additionally, the same study by [84] also demonstrated that proteasome-mediated degradation-induced global DNA hypomethylation can be reversed with adequate treatment with the proteasome inhibitor lactacystin. Lactacystin restored protein levels of DNMT-1, which recovered global DNA methylation. The epigenetic effect of AgNPs on DNA methylation is not only observed in cellular models, but similar effects were also seen in preclinical models. According to a study by [85], in a breast cancer mouse model exposed to AgNP, a significant decrease in methylation levels of DNA and histone H3 was observed. A simultaneous decrease in expression of genes associated with chromatin remodeling and tumorigenesis was also observed. This disruption at the molecular level is not confined to in vitro systems. Comparable levels of epigenetic alterations are also observed in hepatic cell lines, wherein AgNP exposure altered expression of various microRNAs involved in cell proliferation and tumorigenesis pathways [85]. However, on the other hand, AuNPs are known to show epigenetic effects of lower intensity through less production of oxidative stress and genotoxicity [91], as is evident due to lower differences in miRNA profiles and DNA methylation [85]. Stronger toxicity of AgNPs as compared to AuNPs is also evident from a study by [92], wherein AgNPs showed stronger effects on cellular pathways in glioblastoma models as compared to AuNPs. It is worth noting that some studies have demonstrated that the alterations in epigenetic markers after AgNP exposure are visible even after numerous generations. According to a study conducted on the aquatic organism Daphnia magna, AgNP-associated epigenetic effects were observed even in successive generations [86]. However, these observations need to be interpreted carefully, as these cross-generational effects could be different for different experimental models and exposure conditions. Therefore, there is an unmet need to use higher model organisms to confirm whether similar effects are seen across model systems. These observations are clinically relevant because sustained epigenetic modifications may affect long-term therapeutic safety, cellular behavior, and inflammatory responses after chronic exposure to NPs. These findings highlight the fact that better strategies for risk assessment of engineered nanoparticles are required, which extend well beyond acute toxicity to long-lasting epigenetic effects that may also influence clinical safety and regulatory evaluation [93]. Additionally, it is extremely important to standardize exposure conditions in models used for nanoparticle research, especially in studies wherein the nanoparticles are to be used for longer periods of time. Key comparisons in terms of AuNPs and AgNPs are summarized in the Table 5. Greater biocompatibility and stability are generally demonstrated by AuNPs. AgNPs generally demonstrate higher cytotoxicity and stronger antimicrobial activities; however, concerns like oxidative stress, inconsistent biodistribution, and ion-mediated toxicity are also observed. Consequently, it can be suggested that AuNPs and AgNPs may not be used interchangeably as nanoplatforms.

Table 4.

Toxicological effects of AgNPs and AuNPs

Sr. No.	Model System	Nanoparticle (Size/Coating)	Exposure Route	Key Toxicological Findings	Translational Relevance
1	Zebrafish (Danio rerio) embryos	1.3 nm TMAT-functionalized AuNPs	Embryonic immersion	Developmental toxicity including embryo lethality, reduced eye size, hypopigmentation and apoptosis	Demonstrates developmental toxicity of ultrasmall AuNPs during embryogenesis	[82]
2	Zebrafish (Danio rerio) embryos	1.5 nm AuNPs (TMAT-, MES-, MEE-functionalized)	Embryonic immersion	Toxicity varied according to surface chemistry; TMAT induced highest mortality whereas MEE showed minimal toxicity	Highlights importance of nanoparticle surface chemistry in determining biological safety	[88]
3	BALB/c mice	10 nm AuNPs	Intravenous administration with LPS	ROS amplification, macrophage activation and hepatocyte apoptosis aggravated liver injury	Indicates inflammatory status influences AuNP safety in vivo	[43]
4	Drosophila melanogaster	AuNPs	Dietary exposure	Chronic exposure produced heritable phenotypic abnormalities	Suggests potential long-term biological consequences following prolonged exposure	[89]
5	BALB/c male mice	~ 10 nm AgNPs	Repeated intraperitoneal injections	Hepatic necrosis, mitochondrial damage, apoptosis and inflammation	Demonstrates systemic toxicity following repeated exposure	[94]
6	Zebrafish embryos	AgNPs	Waterborne exposure	Reduced hatching, developmental abnormalities, oxidative stress and mitochondrial dysfunction	Developmental toxicity associated with oxidative stress	[97]
7	HFD-induced NAFLD mouse model	AgNPs	Oral administration	Increased steatosis, fibrosis, inflammation and oxidative stress	Indicates higher toxicity in pre-existing liver disease	[83]
8	Human PBMCs	Functionalized AgNPs	Cell culture exposure	Altered cytokine secretion and immune-cell proliferation depending on surface functionalization	Demonstrates immunotoxicity depends on nanoparticle surface properties	[81]
9	Rodent reproductive model	AgNPs	Systemic administration	Blood-testis barrier penetration, oxidative stress and sperm damage	Highlights reproductive safety concerns	[96]
10	Huh-7 cells	Biosynthesized AgNPs	Cell culture exposure	Size-dependent cytotoxicity with mitochondrial dysfunction and membrane damage	Indicates particle size strongly influences toxicity	[98]
11	Zebrafish	AgNPs	Waterborne exposure	Increased ROS, lipid peroxidation, DNA damage and antioxidant depletion	Mechanistic evidence for oxidative stress-mediated toxicity	[90]
12	Human mammalian cell lines	Surface-charged AgNPs	Cell culture exposure	Positively charged AgNPs exhibited greater uptake, lysosomal accumulation and mitochondrial injury	Demonstrates influence of surface charge on intracellular toxicity	[62]

Table 5.

Comparison of pharmacokinetics, ion release, biodistribution, clearance and clinical relevance of AgNPs and AuNPs

Parameter	Gold Nanoparticles (AuNPs)	Silver Nanoparticles (AgNPs)	References
Pharmaco-kinetics	AuNP pharmacokinetics are influenced by particle size, surface chemistry, and functionalization. Following systemic administration, AuNPs are primarily taken up by the reticuloendothelial system and accumulate mainly in the liver and spleen.	AgNP pharmacokinetics depend on particle size, surface coating, and dissolution. Following exposure, AgNPs can be distributed to organs such as the liver, kidney, and spleen.	[83]
Ion release	AuNPs are generally considered chemically stable under physiological conditions and show minimal ion release.	AgNPs can undergo partial dissolution in biological environments, resulting in the release of Ag⁺ ions that contribute to biological activity.	[53, 54]
Biodistribution	Biodistribution studies have shown accumulation of AuNPs mainly in liver and spleen tissues, depending on nanoparticle size and surface characteristics.	AgNPs have been reported to distribute to multiple organs, including liver, kidney, and spleen, in experimental models.	[82, 83]
Clearance	Clearance of AuNPs occurs primarily through hepatobiliary pathways, although exceedingly small particles may undergo renal clearance.	AgNPs may be cleared through hepatobiliary and renal pathways, and dissolution to ionic silver may influence persistence in tissues.	[83, 88]
Biotransformation	AuNPs interact with biomolecules in biological systems, resulting in the formation of a protein corona that influences cellular uptake and biodistribution.	AgNPs can undergo oxidative transformation and partial dissolution, producing ionic silver species in biological environments.	[53, 54]
Regulatory history	AuNPs have been explored in diagnostic imaging, biosensing, and drug delivery platforms, with several systems under investigation for biomedical applications.	AgNPs are widely incorporated into antimicrobial products such as wound dressings and coatings in medical and consumer applications.	[28, 55]
Clinical readiness	AuNPs are being investigated for applications including imaging, theragnostic, and targeted drug delivery due to their tunable physicochemical properties.	AgNPs are commonly used in topical antimicrobial formulations, while systemic therapeutic applications remain under investigation.	[28, 99]

Conclusion

AuNPs and AgNPs demonstrate great potential in being used as tools in imaging, diagnosis, and treating various bacterial, viral, inflammatory, and dermatological conditions and complex diseases like cancer, as these possess unique physicochemical properties, including size, surface functionalization, and surface plasmon resonance (SPR). This review provides a critical comparison between AuNPs and AgNPs by evaluating their respective toxicity profiles, mechanisms of action, biomedical applications, clinical translational potential, and epigenetic modulations. In summary, AgNPs exert stronger cytotoxic and antimicrobial effects mainly through the release of Ag⁺ ions and ROS-associated damage. On the other hand, AuNPs provide better biocompatibility, photothermal functionality, and surface tunability for targeted therapies. However, even with these unique properties, further research is still required to address various issues. In addition, successful clinical translation will require well-designed multicenter clinical trials, standardized physicochemical characterization, GMP-compliant manufacturing, and harmonized regulatory guidelines to ensure clinical efficacy, reproducibility, and safety [10–13]. These include protein corona formation, chronic toxicity, physicochemical instability, inconsistent biodistribution, batch-to-batch variations, insufficient standardized regulatory frameworks, immunotoxicity, and insufficient pharmacokinetic studies before these nanoparticles are translated clinically. Ongoing research has revealed that NPs could also affect epigenetic regulation, oxidative stress pathways, immune system modulation, and cellular homeostasis, which indicates the ambivalent toxicological as well as therapeutic potential of these NPs. The ambivalent nature is because these effects could open new doors for disease treatment, but unwanted use could also cause adverse, heritable changes that include oxidative stress-mediated gene dysregulation and changes in the DNA methylation patterns that pass from progeny to progeny. By this, it can be concluded that successfully translating these NPs for clinical use will require addressing various concerns, including safety, scalability, and reproducibility. Future research needs to prioritize the study of clinically relevant in vivo models, profiling long-term biodistribution patterns, chronic toxicity, quantitative evaluation of structure-activity relationships, and epigenetic modulation. In addition, successful clinical translation will require well-designed multicenter clinical trials, standardized physicochemical characterization, GMP-compliant manufacturing, and harmonized regulatory guidelines to ensure clinical efficacy, reproducibility, and safety [10–13].

Limitations

This review rigorously examines the role of AuNPs and AgNPs in the diagnosis and treatment of various diseases while also focusing on their effects on epigenetic modulation and toxicity. However, there are still various research gaps that need to be addressed before these nanoparticles are incorporated for human use. To address these gaps, long-term in vivo experiments leading to clinical trials are required, especially in the case of AgNPs. Additionally, it is exceedingly difficult to quantitatively collate and compare the results owing to different nanoparticle synthesis techniques, physicochemical characteristics, and biological models studied. Furthermore, this review is limited by its dependence on heterogeneous studies of a preclinical nature. Differences in key NP characteristics, such as experimental models, exposure duration, exposure dosage, and methods of synthesis, also make it difficult to directly compare the interpretations. Therefore, it is essential to note that clinically translating these nanoparticles for diagnosis and treatment in humans requires extensive research on clinical models to mitigate safety concerns. Additionally, due to the scarcity of studies that directly compare AuNPs and AgNPs, it is difficult to determine which metallic NP would be a better option for clinical translation. However, as this is a narrative review rather than a systematic or meta-analysis review, this article lacks a structured process for study selection. Due to this, the risk of selection bias might increase and may complicate quantitative comparison of the findings between studies.

Biographies

Dr. Pratiksha Jadaun

is an Associate Professor of Biotechnology at JSPM University, Pune, with over 18 years of experience in microbiology, virology, and nanoformulations. She holds a Ph.D. in Biotechnology and an M.Sc. in Applied Microbiology, backed by extensive expertise in BSL-2/3 laboratory research. Her core research focuses on antiviral drug discovery, HIV/STIs, marine bioactive compounds, diabetes, and Ayurveda-based therapeutics for infectious and oxidative-stress-related disorders. Previously, she worked with premier national institutes like the National Centre for Cell Science (NCCS) and the Indian Council of Medical Research (ICMR). Dr. Jadaun’s scientific contributions include international publications, patents, and collaborations. Her work has earned her prestigious research fellowships from top Indian scientific bodies, including DST, DHR, CSIR, and ICMR.

Ms. Devangini Sharma

Devangini Sharma is an academic researcher currently pursuing a dual-degree PhD through the SIU-Aston Dual Degree Cotutelle Programme. She is in her second year of doctoral studies at the Symbiosis School of Biological Sciences (SSBS), part of Symbiosis International (Deemed University) in Pune, India. She holds a B.Sc. in Biotechnology from Ganpat University and an M.Sc. in Biology from Indian Institute of Science Education and Research (IISER) Thiruvananthapuram, India. Her research interests include cancer biology, triple-negative breast cancer, oxidative stress, molecular signalling, biomarker discovery, and therapeutic development.

Dr. Joyita Banerjee

Dr. Joyita Banerjee holds a PhD (Faculty of Health Sciences), with doctoral research focused on accelerated ageing associated with type 2 diabetes and the underlying biochemical mechanisms contributing to age-related changes in diabetes. During her Master’s research, she investigated the biosynthesis of silver nanoparticles and their cytotoxic applications, gaining research experience in nanobiotechnology and cellular toxicity. She has contributed to several research publications in reputed peer-reviewed journals. She currently works in the field of oncology variant curation, with expertise in the evidence-based interpretation and clinical annotation of somatic genetic variants. Her research interests encompass cancer genomics, next-generation sequencing, molecular oncology, and genomic medicine, with a focus on integrating functional and clinical evidence for variant interpretation. Her multidisciplinary research experience spans clinical biochemistry, ageing and metabolic disease, and cancer genomics, contributing to the advancement of biomedical research and precision medicine.

Dr. Neetu Mishra

Dr. Neetu Mishra is a Professor at the Symbiosis School of Biological Sciences, Pune, with 20 years of research and teaching experience. from Cancer Hospital & Research Institute, Jiwaji University, Gwalior and Ph.D. in Medical Biochemistry, from G.R. Medical College, Jiwaji University, Gwalior, Madhya Pradesh, India. focusing her doctoral work on diabetes, oxidative stress, and blood viscosity. Her areas of interests are non-communicable diseases; epigenetics, Vitamin D deficiency; Biomarkers; Ageing; Cellular senescence-associated microRNAs; Cardiovascular diseases; inflammation, Nutraceuticals in disease management; micronutrients deficiency. An accomplished author with numerous peer-reviewed articles to her credit, she also contributes to the academic community as a trusted reviewer and editorial board member.

Author contributions

N.M: Conceptualization; Project administration; Supervision; Writing – Review & Editing. J.B: Writing – Original Draft. P.J: Writing – Original Draft. D.S: Writing – Review & Editing; Revision and modification.

Funding

Open access funding provided by Symbiosis International (Deemed University).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Not applicable. This article does not report any studies involving human or animal.

Competing interests

The authors declare no competing interests.