A medical condition known as cancer is characterized by abnormal development of cells or tissues. It is challenging to combat cancer, especially when developing treatments for tumors that are rapidly proliferating (Shunmugam et al., 2021). The International Agency for Research Cancer (IARC) estimates that one in five people acquires cancer in their lifetime worldwide. The GLOBACAN is an online database that provides the global cancer statistics data. According to GLOBACAN 2020 data, there were approximately 19.3 million new cancer cases and 10 million cancer-related deaths worldwide. Recently, lung and prostate cancer have been the most common among men, while women most frequently face colorectal, lung, cervical, and thyroid cancers (Sung et al., 2021). The 2023 report from the American Cancer Society and the National Centre for Health Statistics recorded 1,958,310 new cancer cases and 609,820 cancer deaths in the United States (Siegel et al., 2023). Traditional cancer treatments such as surgery, chemotherapy, and radiation have been shown to pose significant risks to human health. Therefore, targeted drug delivery combined with controlled release technology, which is more efficient and harmful-free, is needed in place of current approaches (Rajeshkumar, 2016).

Nanotechnology is being employed in medicine to create novel antibacterial and anti-cancer medicines to provide more effective cancer therapies and prevention methods. Since the early 2000s, extensive research has focused on the use of nanoparticles as a promising approach for cancer treatment. Currently, there is significant interest in the synthesis of metal nanoparticles, particularly gold nanoparticles, due to their superior biological compatibility and low toxicity. Their photophysical and optical properties make gold nanoparticles valuable for chemotherapy and cancer diagnostics. Gold nanoparticles (Au NPs) offer several advantages over other nanoparticles in cancer therapy. Their biocompatibility, minimal toxicity, and size tunability make them ideal candidates for drug delivery systems. Au NPs have strong optical and physical properties, making them highly effective for diagnostic imaging and therapeutic applications such as photothermal therapy and radiosensitization. Furthermore, Au NPs can be functionalized with various targeting ligands, enhancing their selectivity and enabling precise delivery to cancer cells, minimizing damage to healthy tissues​. Their ability to act as diagnostic and therapeutic agents (“theranostics”) further enhances their versatility in cancer treatment. Recent studies highlight the growing focus on gold nanoparticles for their potential to work synergistically with immunotherapy. This combination shows significant promise in improving early cancer diagnosis and enhancing overall treatment outcomes by boosting immune responses and offering better control over tumor progression (Goddard et al., 2020; Sultana et al., 2023). AuNPs demonstrate significant antimicrobial activity, effectively inhibiting various pathogens and biofilm formation, making them promising as alternative antimicrobials. Moreover, their wound healing potential is evident in enhanced cell migration and proliferation, aiding tissue repair and offering anti-inflammatory benefits. AuNPs also show great promise in biosensing and diagnostics due to their unique optical properties, enabling sensitive detection of biomolecules for early disease diagnosis (Mikhailova, 2021).

The synthesis of gold nanoparticles can be achieved through physical, chemical, and biological methods, including the use of plants and microorganisms. In comparison to other methods, plant-mediated nanoparticle production is preferred because it allows for the utilization of physiologically active plant components as essential raw materials (Rana et al., 2023). Furthermore, this method does not necessitate labor-intensive intracellular manufacturing procedures, numerous purifications, or the upkeep of microbial cells (Tomar and Garg, 2013; Hanan et al., 2018). Several studies have been reported on the use of plants and their part extracts for gold nanoparticle synthesis and their potential activities as anticancer agents. The gold nanoparticles synthesized using Tecoma capensis (L.) leaf extract have shown potent anticancer activity against the growth and proliferation of human breast cancer cell lines (Hosny et al., 2022). It has been studied that the spherical-shaped gold nanoparticles synthesized using Dracocephalum kotschyi leaf extract possessed great anticancer activity against HeLa and K562 cell lines (Dorosti and Jamshidi, 2016). The plants Marsdenia tenacissima, Halymenia dilate, Nerium oleander, Lonicera japonica, Pleuropterus multiflorous, and Dendropanax morbifera have also been found to synthesize gold nanoparticles with anticancer characteristics (Sun et al., 2019; Vinosha et al., 2019; Barai et al., 2018; Patil et al., 2019; Castro-Aceituno et al., 2017; Wang et al., 2016). This study intends to highlight the overall synthesis of plant-mediated gold nanoparticles, their anticancer properties in both in vitro and in vivo settings, and the mechanisms involved. Additionally, the study emphasizes the drug delivery potential, biocompatibility, and toxicity of synthesized gold nanoparticles, while also discussing their future prospects and associated obstacles.

The process of synthesizing gold nanoparticles (AuNPs) using plants and their extracts (Figure 1) has attracted significant interest owing to their distinctive properties and diverse applications, particularly in the field of medicine. This type of synthesis approach is facile, cost-effective, and eco-friendly, in that the particles can act as sensors, catalysts, etc. with regulated crystal growth and stability. The biochemical compounds found in the plant extract act as agents that reduce, stabilize, and cap the gold nanoparticles during their synthesis. These include proteins, carbohydrates, organic acids, enzymes, flavonoids, phenolics, alkaloids, vitamins, etc. These biomolecules are essential for converting chloroaurate ions into metallic gold and for stabilizing them at the nanoscale. Gold nanoparticles synthesized from plant extracts typically range in size from 1 to 100 nm and predominantly exhibit a spherical morphology. However, triangular, oval, hexagonal, polygonal, irregular, or rod-shaped particles were also found (Sargazi et al., 2022; Dash et al., 2022). The selection of plant extract, its concentration, the type and amount of precursor or salt, pH level of the medium, incubation temperature, and reaction duration are critical factors influencing the quantity, specific shape, and size of the synthesized nanoparticles. (Teimouri et al., 2018). For example, a previous study used Eucalyptus globulus Labill bark aqueous extract to examine the different factors responsible for the shape and size of synthesized gold nanoparticles. The results concluded that the pH of the medium and concentration of the extract are the primary key factors for the controlled size and shape of the synthesized nanoparticles. However, the temperature and reaction time showed moderate effects on their morphology. According to this work, several experimental conditions can affect the shape and size of greenly synthesized AuNPs (Pinto et al., 2017). In another study, gold nanoparticles were synthesized using Cucurbita pepo leaf extract at relatively low temperatures (70°C). The results indicated that the shape and size of the nanoparticles were related to the concentration of chlorophylls and carotenoids in the extracts. The Transmission electron microscopy results showed the development of anisotropic nanoparticles with lower gold concentration whereas a large production of monodisperse AuNPs with sizes between 10 and 15 nm is encouraged by higher concentrations (Gonnelli et al., 2018).

There are Various methods have been reported for the plant-mediated synthesis of gold nanoparticles such as the use of aqueous extracts, enzymatic reduction, microwave-assisted, ultrasonication, and solar irradiation (Table 1). Aqueous gold salt solutions, such as chloroauric acid (HAuCl4), are combined with plant extracts, which are commonly derived from leaves, stems, or roots. The reduction of gold ions is facilitated by phytochemicals present in plant extracts. For instance, the aqueous extract of Momordica cochinchinensis rhizome has been used as a reducing and stabilizing agent in the synthesis of gold nanoparticles at room temperature. When 1 mL of the extract was added to 20 mL of a 0.01 mM gold solution, it reduced the gold ions, resulting in the formation of gold nanoparticles. UV-visible spectroscopy results confirmed the color change to ruby red, indicating the excitation of surface plasmon resonance in the nanoparticles. The FTIR spectrum revealed the presence of phenolic acids and flavonoids, which are responsible for reducing and stabilizing the nanoparticles. These compounds facilitate the conversion of precursor gold ions into small metal ions (Lakshmanan et al., 2016). The aqueous peel extract of Garcinia mangostana and the bark extract of Mimusops elengi have also been reported as effective reducing and stabilizing agents for the synthesis of gold nanoparticles. When combined with an aqueous gold solution, these extracts facilitated the reduction of gold ions, forming gold nanoparticles. FTIR spectrum analysis confirmed the presence of benzophenones, anthocyanins, polyphenols, and flavonoids which served as both reducing and stabilizing agents. Furthermore, gold nanoparticles mediated by M. elengi bark extract have been utilized as strong catalysts for reducing 3-nitrophenol and 4-nitrophenol in water at room temperature (Xin Lee et al., 2016; Majumdar et al., 2016) Figure 2 is showing the physiochemical characteristics of plant mediated gold nanoparticles synthesized using leaf extract of Moringa oleifera. In the process, 4 mL of the extract was mixed with 20 mL of gold chloride solution, leading to a noticeable color change, signifying the formation of AuNPs. The nanoparticles, with sizes ranging from 14 to 30 nm, were characterized using techniques like TEM and DLS, confirming their spherical morphology and stable size distribution. The characterization data highlights these features. Additionally, UV-Vis spectroscopy displayed a surface plasmon resonance peak between 520–540 nm, confirming nanoparticle formation. The AuNPs also showed effective biological and photocatalytic activities, making them potential candidates for diverse applications (Boruah et al., 2021).Microwave irradiation is one of the rapid, facile, and laid-back techniques for the formation of plant-mediated gold nanoparticles. When compared to conventional heating methods, microwave assistance offers many advantages including quicker reaction times, faster reaction rates, better product yields, and lower energy consumption. In this method, the plant extracts are combined with a gold-containing salt solution and microwave irradiated which results in rapid synthesis of AuNPs (Punnoose et al., 2021). Recently, Mimosa diplotricha leaf extract has been employed for the microwave-assisted synthesis of AuNPs. In this process, 10 mL of the leaf extract was combined with 90 mL of a 1 mM auric trichloride solution and subjected to microwaving in a standard domestic oven. The results showed that with 1 min of microwave heating the light-colored blend changes to violet color. The presence of the characteristic peak at 548 nm indicated the complete reduction of gold ions (Au³⁺ to Au⁰). Also, the FTIR spectroscopy confirms the presence of phenolic groups in the leaf extract (Punnoose and Mathew, 2022). Similar to this, it has also been claimed that Jatropha curcas, Myristica fragrans, green tea, Caesalpinia sappan, Oroxylum indicum, and aloe leaf extract all contributed to the formation of gold nanoparticles. Moreover, the phytoconstituents present in the extracts functioned as capping, reducing, and stabilizing agents (Francis et al., 2018; Punnoose et al., 2021; Serdar and Kılınç, 2023; Thanayutsiri et al., 2023; Worakitjaroenphon et al., 2023; Parimala et al., 2022). Ultrasonication is one of the most efficient methods for the production of small-sized nanoparticles. In this method, the ultrasonicated waves promote the reduction of gold ions by the plant extracts. Recently, gold nanoparticles with ultrasonic assistance were made using Citrus sinensis peel extract. It was observed that the use of ultrasound reduced the distribution and size of the synthesized NPs while enhancing their yield and stability. Additionally, hesperidin was identified as the primary reducing agent for the NPs (Gao et al., 2022). The leaf extract of Nothapodytes foetida has been utilized for the ultrasonication-assisted synthesis of gold nanoparticles. This process resulted in the formation of spherical and crystalline nanoparticles with diameters ranging from 5 to 30 nm. The nanoparticles exhibited excellent stability, attributed to their negative zeta potential (Susanna et al., 2023). The flower extract of Clitoria ternatea has been documented for the synthesis of gold nanoparticles via ultrasonication, serving as a reducing agent in the process. By using ultrasound irradiation, small-size nanoparticles formed with a size range of 18–50 nm in a short time (Fatimah et al., 2020). Considering ultrasonication can control particle size and improve stability, it is the most effective approach for creating homogenous AuNPs in plant-mediated synthesis. Citrus sinensis and N. foetida extracts show that this technique efficiently reduces size distribution and produces very uniform nanoparticles in the 5–30 nm range.

Several potential anticancer mechanisms of green-synthesized NPs have been identified. These mechanisms include selective targeting, induction of apoptosis, inhibition of angiogenesis, generation of reactive oxygen species, mitochondrial dysfunction, enhancement of drug delivery, and photothermal therapy (Figure 3) (Bharadwaj et al., 2021). Several publications suggest that gold nanoparticles (AuNPs) exhibit various interactions with cells, with numerous researchers documenting the internalization of AuNPs by cellular entities. The surface properties of gold nanoparticles (AuNPs) play a crucial role in the process of cellular internalization. The cellular uptake and internalization of AuNPs can be accredited to the electrostatic attraction resulting from the opposing charges exhibited by AuNPs and the cell membrane. Gold nanoparticles (AuNPs) possess positive charges, whereas the membranes of cancer and normal cells consist of lipids, particularly phosphate groups, which are negatively charged (Gong et al., 2015; Albanese et al., 2012). Moreover, certain research has indicated that the internalization of gold nanoparticles occurs via the process of endocytosis (Cui et al., 2012). Once inside the mitochondria, they follow various pathways that impact the electron transport chain, induce structural damage, activate NADPH enzymes, and depolarize mitochondrial membranes (Xia et al., 2006; Sun et al., 2018). In malignant cells, AuNPs increase intracellular ROS levels which leads to permanent oxidative harm, DNA degradation, and cellular demise through several routes such as apoptosis, autophagy, or necroptosis (Redza-Dutordoir and Averill-Bates, 2016). Gold nanoparticles (AuNP) have been found to induce mitochondrial malfunction and trigger apoptosis through a caspase-dependent pathway. The mitochondria are the primary cellular organelles that experience damage during apoptosis mediated by reactive oxygen species (ROS). As a result of oxidative stress and membrane permeabilization, mitochondria have been observed to release specific cell death-related chemicals into the cytosol and nucleus, including cytochrome-c, Apoptosis-Inducing Factor (AIF), and Endonuclease G (ENDO-G) (Zorov et al., 2014; Wang and Youle, 2009).

One of the studies demonstrated the anticancer effect of M. tenacissima-mediated gold nanoparticles against lung cancer cells. The gold nanoparticles triggered apoptosis in cancer cells by down-regulating the expression of Bid and Bcl-2, while up-regulating the expression of caspase-8, caspase-9, caspase-3, and Bax (Sun et al., 2019). In a recent study, gold nanoparticles mediated by Tecoma capensis (L.) induced apoptosis in breast cancer cells, leading to cell shrinkage or cell death. The synthesized nanoparticles penetrate the cell membrane, interact with, and disrupt other biomolecules like proteins, nucleic acids, and other compounds (Hosny et al., 2022). AuNPs produced by plants can cause cancer cells to produce reactive oxygen species (ROS). High ROS concentrations can damage biological components, induce oxidative stress, and eventually result in cell death. The gold nanoparticles synthesized using the Syzygium aromaticum extract induced apoptosis in the SUDHL-4 cell lines through ROS production (Parida et al., 2014). Similarly, the Rhus chinensis mediated gold nanoparticles induced apoptosis to the Adenocarcinoma (MKN-28), Hepatocellular carcinoma (Hep3B), and Osteosarcoma (MG-63) cells through the DNA fragmentation or DNA damage (Patil et al., 2017). Furthermore, M. oleifera-mediated AuNPs induced caspase-mediated cell death in A549 cells, as indicated by elevated activities of caspase-9 and caspase-3/7, a substantial decrease in ATP levels, and a significant increase in the protein concentrations of p53 and Bax (Tiloke et al., 2016). The gold nanoparticles synthesized using Cynodon dactylon aqueous extract have shown probable anticancer activity against human breast cancer cells and are nontoxic to normal cells. The inhibitory effect was found to be dose-dependent, with green-synthesized AuNPs exhibiting an IC50 value of 31.34 μg/mL. Post-treatment, ROS levels increased, leading to programmed cell death in MCF-7 cancer cells. Results from rhodamine staining, AO/EtBr staining, and DAPI labeling indicated significant mitochondrial membrane damage and DNA fragmentation, suggesting apoptosis in the cancer cell lines (Vinayagam et al., 2021). Another study was conducted that showed the environment-friendly efficacy of Commiphora wightii-mediated AuNPs against human cancer cell lines. The results of in vitro cytotoxicity assays showed cell cycle arrest at the G2/M phase, which subsequently triggered apoptosis (Uzma et al., 2020). Moreover, through surface modification, AuNPs can attach to other materials covalently or non-covalently. Molecules can adhere to AuNPs non-covalently by a variety of interactions, including particular binding affinities, electrostatic interactions, and hydrophobic interactions. That’s why gold nanoparticles are also used as transporters for anticancer drugs. They can deliver the chemotherapeutic drugs directly to the targeted tumour site which further reduces the risk of systematic toxicity of the drug. The Punica granutum fruit peel extract-mediated monodispersed AuNPs have been used as carriers for targeted drug delivery for MCF-7 cancer cell lines. The synthesized nanoparticles functionalized with folic acid showed in vitro cytotoxicity in the cancer cells via DNA fragmentation and induced G0/G1-phase cell cycle arrest. These findings imply that p21WAF1-induced G1-phase cell cycle arrest and growth suppression in MCF-7 must be mediated through the JNK/ERK signaling pathway (Ganeshkumar et al., 2013). Gold nanoparticles mediated by Vitex negundo were synthesized using leaf extract as a reducing agent and Arabic gum as a stabilizing agent. Folic acid was subsequently added to the nanoparticles to specifically target A549 lung cancer cells. It was found that the folic acid functionalized nanoparticles increased the cytotoxic effect by targeting the cells and also raised the epirubicin uptake by the cancer cells (Renuga Devi et al., 2015). Another study examined the potential of pectin-mediated AuNPs as chemotherapeutic medication carriers in drug delivery systems. Pectin, a natural polysaccharide, functions as both a reducing and stabilizing agent. In vitro assays demonstrated that doxorubicin (DOX) loaded onto pectin-derived AuNPs (pec-AuNPs) exhibited a significantly greater lethal effect on breast cancer cells compared to DOX alone. The study also suggested that AuNPs decorated with chitosan-folic acid could serve as biocompatible nanocarriers for delivering cancer-specific medications (Devendiran et al., 2016).

The process by which new blood vessels are produced is called angiogenesis. One method for depriving tumors of nutrition and oxygen is to inhibit angiogenesis. AuNPs may hinder the angiogenesis-related signaling pathways. An in vitro study investigated the impact of gold nanoparticles synthesized using Mangifera indica seed extract on human gastric cancer cells. The gold nanoparticles demonstrated significant anticancer properties by disrupting the cell membrane and inducing cell cycle arrest. Furthermore, an in vivo study done on chick embryos concluded that the antiangiogenic effect of synthesized gold nanoparticles by targeting the Ang-1 and Tie2 pathways (Vimalraj et al., 2018).

AuNPs with maximal absorption in the visible or near-infrared region absorb light and produce heat. This characteristic can be used in photothermal therapy, which uses light-induced heating of AuNPs to specifically target and kill cancer cells. Spherical solid gold nanoparticles (AuNPs) exhibiting a diameter above 50 nm, owing to their pronounced near-infrared (NIR) absorption capabilities, are frequently observed in photothermal therapy (Mishra et al., 2016). An aqueous method was used to produce NIR-absorbing anisotropic gold nanoparticles, utilizing cocoa extract as a reducing and stabilizing agent. These gold nanoparticles were then subjected to density gradient centrifugation to enhance their near-infrared (NIR) absorption within the 800–1,000 nm wavelength range. In vitro results demonstrated significant anticancer effects at concentrations up to 200 μg/mL against MDA-MB231, L929, A431, and NIH-3T3 cell lines. Also, Cell death was observed in A431 epidermoid carcinoma cells when exposed to irradiation from a femtosecond laser operating at a wavelength of 800 nm and a low power density of 6 W/cm² (Fazal et al., 2014). In one of the studies, apigenin-coated AuNPs with a diameter of 19.1 nm were synthesized and showed a significant photothermal effect on cancerous cells by inducing apoptosis. Based on the obtained findings, the application of in vitro photothermal therapy (PTT) for a duration of 3 min, using apigenin-coated gold nanoparticles at a concentration of 128 μg/mL, results in around 50% mortality rate for both mouse fibroblastic and colorectal cancer cells (Amini et al., 2021). Recently, rutin-mediated gold nanoparticles coupled with laser radiation have been used to check out their photothermal effect against breast cancer cell lines. Rutin, a highly abundant flavonoid glycoside found in R. graveolens L., was utilized as a reducing and capping agent in the study. The findings demonstrated that Au NPs produced using Rutin, in combination with laser radiation (150 J/cm² for 300 s), exhibited a significant and effective photothermal therapy (PTT) anticancer effect on MCF-7 cells (Shabani et al., 2023). Conclusively, AuNPs with a size between 30 and 50 nm are excellent for cancer therapy. The increased permeability and retention (EPR) effect helps this size, which facilitates better drug transport, less systemic toxicity, and better tumor accumulation. This family of AuNPs further enhances photothermal therapy, providing increased therapeutic efficacy and tumor-targeting efficiency.

Biomolecules such as receptors, proteins, carbohydrates, and polyphenolic compounds can be conjugated to AuNPs via surface modification techniques. This modification grants AuNPs specific functionalities such as nano-bioconjugates, rendering them suitable for applications in biomedicine, particularly targeted drug delivery (Lee et al., 2008). As a result, they can specifically target tumor cells through receptor-mediated endocytosis, a process known as active targeting (Fadeel and Garcia-Bennett, 2010; Sezgin et al., 2008). Furthermore, nanoparticles synthesized biosynthetically are naturally coated with biomolecules extracted from plants, which can act as carriers for delivering biomolecules. Due to their large surface area, AuNPs have significant conjugation capabilities and can bind with various chemical compounds, including drugs and other biomolecules. Therefore, AuNPs synthesized through biological methods can be modified by biological peptides from plant extracts, serving as natural connectors for delivering drugs to specific cells or tissues (Heegaard et al., 2007). Moreover, the biocompatibility of AuNPs synthesized through green methods extends to both normal and abnormal cells, rendering them indispensable as carriers for drug delivery. Utilizing these green-synthesized AuNPs, a drug delivery system (DDS) based on gold has been developed, incorporating the FDA-approved anticancer drug doxorubicin. This system has demonstrated superior therapeutic efficacy compared to the drug administered alone. The heightened effectiveness of the DDS may stem from increased specificity, as well as enhanced permeability and retention (EPR) effects (Patra and Baek, 2015). Here are some potential drug delivery applications of PM-AuNPs.

Through comprehensive assessments encompassing biocompatibility, physicochemical properties, dosage, exposure routes, and environmental fate, researchers strive to elucidate the intricate nuances surrounding the safety profile of these nanomaterials, particularly in the context of medical applications.

In conducting compatibility studies, researchers delve into the intricate interplay between plant-mediated AuNPs and biological systems. Employing a diverse array of in vitro and in vivo models, investigations aim to elucidate the impacts of AuNPs on cellular function, organ systems, and overall health. These studies not only shed light on the biocompatibility of AuNPs but also serve to identify potential mechanisms underlying any observed effects, thus facilitating informed decision-making regarding their biomedical utility. Furthermore, the physicochemical properties of AuNPs serve as critical determinants of their biocompatibility and toxicity profiles. Through meticulous characterization utilizing advanced techniques such as transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis, researchers unravel the intricate morphological and surface characteristics of AuNPs. By scrutinizing parameters such as size, shape, surface charge, and coating composition, researchers gain invaluable insights into the factors governing the interactions between AuNPs and biological entities, thereby informing strategies for enhancing their compatibility and mitigating potential adverse effects. Dosage and exposure routes represent additional dimensions that warrant meticulous scrutiny in assessing the safety profile of plant-mediated AuNPs for medical applications. Studies systematically explore the effects of varying concentrations and exposure durations across diverse biological systems, encompassing routes such as oral, inhalation, and dermal exposure. Through meticulous experimentation, researchers aim to delineate the dose-response relationships and ascertain threshold levels beyond which adverse effects may manifest, thus facilitating the establishment of guidelines for safe usage in medical settings. Moreover, the biodegradation and environmental fate of plant-mediated AuNPs represent critical facets that necessitate thorough investigation to comprehensively assess their safety profile. By scrutinizing factors such as persistence, transformation, and potential accumulation in ecosystems, researchers gain insights into the long-term environmental implications of AuNP utilization. Furthermore, elucidating the interactions of AuNPs with environmental matrices and biota enables a holistic understanding of their ecological footprint, thereby informing strategies for minimizing environmental impact.

In essence, the amalgamation of compatibility studies, physicochemical characterization, dosage assessment, and environmental fate analysis culminates in a comprehensive evaluation of the safety profile of plant-mediated AuNPs for medical use. Green-synthesized gold nanoparticles (AuNPs) have emerged as a fascinating field of study within biomedical research, offering a myriad of potential applications owing to their eco-friendly production methods and unique properties. These nanoparticles, synthesized using plant extracts, have attracted considerable attention for their biocompatibility and therapeutic potential across diverse areas such as drug delivery, imaging, cancer therapy, and antibacterial treatments. Unlike their chemically synthesized counterparts, green-synthesized AuNPs exhibit reduced cytotoxicity and improved compatibility with biological systems, positioning them as promising candidates for safer and more effective biomedical interventions. A seminal study by (Rónavári et al., 2021) illuminated the superior biocompatibility of plant-mediated AuNPs compared to chemically synthesized counterparts. Their investigation revealed that AuNPs synthesized via green methods displayed reduced cytotoxic effects on mammalian cell lines while demonstrating efficacy in inhibiting the growth of cancer cells, all while exerting minimal toxicity to normal cells. This pivotal research underscored the therapeutic promise of green-synthesized AuNPs, positioning them as viable options for various biomedical applications.

The eco-friendly synthesis of AuNPs utilizing plant extracts offers numerous advantages (Patil and Chandrasekaran, 2020). elucidated the stability and reduced toxicity of biogenic AuNPs, attributing these qualities to the natural capping agents present in plant extracts. These agents serve to prevent nanoparticle aggregation and enhance cellular uptake without inducing harm, thereby enhancing the overall biocompatibility of the nanoparticles. Additionally (Roy et al., 2022), expounded upon the enhanced biocompatibility and stability of biogenic AuNPs, advocating for their utility across a broad spectrum of biomedical applications, including drug delivery and imaging. Critical to the advancement of green-synthesized AuNPs for clinical use is the comprehensive assessment of their safety profile emphasizes the significance of standardized protocols in evaluating the biocompatibility and cytotoxicity of AuNPs. Generally, green-synthesized nanoparticles exhibit lower cytotoxicity and higher biocompatibility compared to their chemically synthesized counterparts, rendering them safer for medical applications (Bailly et al., 2019). conducted in-depth in vivo evaluations elucidating the safety, biodistribution, and pharmacokinetics of AuNPs, revealing minimal adverse effects and effective clearance mechanisms. The functionalization of AuNPs further augments their stability and biocompatibility. Moreover, studies by (Akkam et al., 2023) delved into the fate and toxicity of green-synthesized AuNPs in animal models, revealing minimal toxicity and effective clearance mechanisms, particularly by the liver and spleen. In the realm of cancer therapy, AuNPs offer unparalleled advantages. Furthermore (Akouibaa et al., 2024), delved into the fate and toxicity of green-synthesized AuNPs in albino mice, offering valuable insights into their biocompatibility and distribution within living organisms. This research provides crucial information for understanding the systemic effects of AuNPs and assessing their safety for clinical use (Table 4). (Pannerselvam et al., 2020) prepared gold nanoparticles (AuNPs) from ten Cassia species, with C. roxburghii producing the most efficient and stable AuNPs. Optimal conditions were pH 7.0, 37°C, 1.0 mL of C. roxburghii leaf extract, and 1.0 mM HAuCl4, resulting in ∼50 nm particles stable for 12 months. In-vivo safety was tested by intravenous injection in male Wistar albino rats. No significant changes were observed in body weight, hematological and biochemical parameters, or histopathology of vital organs. The highest accumulation was in the spleen, least in the brain. The AuNPs were biocompatible with no adverse effects noted, but long-term bioaccumulation needs further study (Pannerselvam et al., 2020). One of the study reported the green synthesis of stable, well-characterized gold nanoparticles (CAuNP) using Calotropis gigantea floral extract and investigated their in vivo biocompatibility compared to commercial AuNPs in a zebrafish embryo model. The LC50 of CAuNPs was 69 ± 12 μg/mL, compared to 52 ± 6 μg/mL for commercial AuNPs. Gold nanoparticles caused concentration-dependent morphological abnormalities and acute cellular and molecular effects. Both experimental and computational analyses showed nanotoxicity due to oxidative stress, leading to apoptosis through interactions with Sod1, He1a, and tp53 mRNA and proteins. This study highlighted the nanotoxicity of gold nanoparticles and suggested the potential of green synthesis methods for future production (Verma et al., 2018). In one of the studies, gold nanoparticles (AuNPs) were biosynthesized using leaf tissue from Isodon excisus (Maxim.) Kudo (IE). Transmission electron microscopy (TEM) images revealed that the AuNPs had sizes ranging from 10 to 100 nm and exhibited polygonal, triangular, and hexagonal shapes. Additionally, the cytotoxicity of IE-AuNPs on human keratinocytes (HaCaT cells) was evaluated, showing that the IE-AuNPs, at a concentration of 50 μg/mL, did not exhibit any cytotoxic effects on HaCaT cells (Dhandapani et al., 2023).

The field of plant-mediated gold nanoparticles (AuNPs) faces several multifaceted challenges and limitations across synthesis, characterization, and application stages. Inconsistencies in synthesis arise due to the variability in biochemical composition of plant extracts, which can change based on factors such as plant species, part used, age, and growing conditions. This leads to variations in size, shape, and yield of the nanoparticles, posing a significant hurdle for large-scale production and ensuring reproducibility. The complexity of plant extracts, containing a mixture of bioactive compounds like proteins and polyphenols, complicates the understanding and control of the synthesis process, making it difficult to optimize conditions for desired nanoparticle properties.

Stability and shelf-life of plant-mediated AuNPs present another challenge, as these nanoparticles are prone to aggregation and changes in physicochemical properties over time, affecting their efficacy in applications. Ensuring long-term stability without compromising biocompatibility is crucial. Additionally, scaling up production from laboratory to industrial scale while maintaining quality and consistency requires the development of new protocols and technologies capable of handling the increased volume and complexity. Concerns about biocompatibility and potential toxicity of AuNPs remain significant. Although plant-mediated synthesis is generally considered more environmentally friendly and less toxic than chemical methods, thorough understanding of interactions with biological systems is necessary. Comprehensive toxicity studies are essential to ensure safe use, particularly in biomedical applications like cancer treatment. Furthermore, evaluating the environmental impact of AuNPs, including their fate and behavior in ecosystems, is critical to prevent bioaccumulation and unintended harm to non-target organisms.

Despite these challenges, plant-mediated AuNPs hold substantial potential. Their unique properties, including biocompatibility, ease of functionalization, and enhanced permeability and retention in tumor tissues, make them suitable for these uses. In cancer theranostics, AuNPs can act as both therapeutic and diagnostic agents. They can be engineered to target tumors specifically, reducing side effects and improving treatment efficacy. For diagnostics, AuNPs enhance imaging techniques such as MRI, CT scans, and photoacoustic imaging, enabling high-resolution images and early tumor detection. Moreover, the optical characteristics of AuNPs, including surface plasmon resonance, render them suitable for photothermal therapy (PTT). During PTT, AuNPs accumulate at tumor sites and convert near-infrared light into heat, effectively destroying cancer cells. This approach provides a targeted and non-invasive treatment option with minimal impact on healthy tissues.

Future research must address several key areas to fully realize the clinical potential of plant-mediated AuNPs. Standardization and optimization of the synthesis process are critical to achieving consistent size, shape, and functional properties. Researchers should focus on standardizing the phytosynthesis process by optimizing parameters such as plant species, extraction methods, and reaction conditions to ensure reproducibility and scalability. Comprehensive toxicity studies are essential to understand the long-term effects on human health, including the biodistribution, metabolism, and excretion of these nanoparticles. Further research is also needed to elucidate the exact mechanisms by which plant extracts facilitate AuNP formation, which can lead to more controlled and efficient synthesis methods.

Assessing the environmental impact of increasing AuNP production and use is also crucial. This includes studying their biodegradability and ecological effects to develop strategies for minimizing environmental footprints. Interdisciplinary collaboration among chemists, biologists, medical researchers, and environmental scientists will be vital in overcoming these challenges and accelerating the translation of laboratory findings into clinical and industrial applications. By addressing these areas, researchers can pave the way for the safe and effective clinical use of plant-mediated AuNPs, harnessing their full potential for various biomedical applications.

The green synthesis of AuNPs using plant extracts has emerged as a transformative approach in cancer research, offering numerous significant findings and implications. This eco-friendly and sustainable method leverages the natural reducing and stabilizing agents present in plants, resulting in the production of biocompatible nanoparticles that exhibit potent anticancer properties. These plant-mediated AuNPs have demonstrated remarkable efficacy in inhibiting cancer cell proliferation and inducing apoptosis across various cancer cell lines, showcasing their potential as effective anticancer agents. The unique optical and electronic properties of these AuNPs, derived from their nanoscale dimensions and surface characteristics, enhance their utility in both therapeutic and diagnostic applications. For instance, in cancer diagnostics, these nanoparticles improve the sensitivity and specificity of imaging techniques such as MRI, CT scans, and photoacoustic imaging. This capability allows for more accurate tumor detection and monitoring, facilitating early diagnosis and precise treatment planning.

In therapeutic applications, plant-mediated AuNPs have shown great promise in enhancing the delivery of chemotherapeutic drugs. By conjugating these nanoparticles with anticancer drugs, targeted delivery to tumor cells is achieved, increasing the drugs’ therapeutic efficacy while minimizing systemic side effects. Additionally, these nanoparticles play a critical role in advanced treatment modalities such as photothermal therapy (PTT) and photodynamic therapy (PDT). In PTT, the AuNPs absorb near-infrared light and convert it into heat, effectively killing cancer cells localized in the tumor. When combined with PDT, which involves light-activated drugs producing reactive oxygen species to destroy cancer cells, the overall therapeutic outcome is significantly improved, offering a synergistic effect with minimal damage to surrounding healthy tissues. Moreover, the integration of plant-mediated AuNPs in immunotherapy is an exciting avenue for future research. These nanoparticles can be engineered to deliver immunomodulatory agents directly to the tumor microenvironment, enhancing the body’s immune response against cancer cells and potentially improving the effectiveness of existing immunotherapies. The dual functionality of these AuNPs in combating both cancer and other diseases further underscores their broad-spectrum applicability. For example, studies have shown that these nanoparticles not only exhibit anticancer activity but also possess antimicrobial properties, making them versatile tools in the fight against various health challenges.

Henceforth, the green synthesis of gold nanoparticles using plant extracts represents a significant advancement in cancer research. This approach offers a sustainable, biocompatible, and multifunctional platform for developing innovative cancer therapies. The continued exploration and optimization of these biogenic synthesis methods hold great promise for enhancing the efficacy and safety of cancer treatments, paving the way for their integration into clinical practice. As research progresses, the potential for these nanoparticles to revolutionize cancer therapy and diagnostics becomes increasingly apparent, highlighting the importance of interdisciplinary collaboration in realizing their full potential.