Functionalized AuNPs undergo LSPR peak shifts and visible color changes upon binding target molecules. AuNPs-based colorimetric assays thus exploit this phenomenon to assess levels of cervical cancer biomarkers through readily observable color transitions (31). microRNA-378 is consistently dysregulated in cervical cancer. Run and colleagues developed a colorimetric assay using catalytic hairpin assembly (CHA) and AuNPs for its detection (31). Target miRNA-378 triggers CHA between two hairpin probes, generating polymeric products. Multiple polyadenine blocks on these products adsorb and cross-link AuNPs (~13nm, Citrate-reduced) under acidic conditions, inducing aggregation. This shifts the LSPR, causing a visible color change from red to purple ( Figure 1 ) (31). The assay leverages nucleic acid hybridization specificity, offering operational simplicity, high sensitivity, and strong specificity, with a LOD of 20.7 pM (31).

Motivated by the high cost of target-specific AuNP functionalization, label-free C-ColAur was developed as an alternative (32). Label-free C-ColAur is a nonspecific detection method leveraging AuNPs color shifts from LSPR. Target binding protects AuNPs from salt-induced aggregation, enabling rapid on-site pathogen screening via visible color changes, particularly in resource-limited settings (32). Applied to cervicovaginal fluid, it shows distinct color changes: AuNPs turn blue in healthy samples but remain unchanged in cancer samples, achieving high diagnostic accuracy (96% sensitivity, 87% specificity; Figure 2 ) (33). Transmission Electron Microscope (TEM) revealed significantly larger AuNP diameters (250~400nm, Citrate-reduced, Quasi-Spherical) in patients versus controls (15~30nm, Citrate-reduced, Quasi-Spherical), with reduced particle numbers and absence of aggregation in cancer samples (33). Tejaswini et al. proposed that cancer cell membrane components induce aggregation (34). Experimental validation confirmed that synthetic lipids, but not proteins or lipid-protein mixtures, replicated the color or spectral shift when reacted with HAuCl₄·3H₂O and ascorbic acid, indicating lipid-specific organization drives the mechanism (34).

HR-HPV is the primary cause of cervical cancer. Conventional detection (qPCR, isothermal amplification, dot blot) faces limitations including contamination risk, incomplete subtyping, and high cost (35). AuNP-based colorimetric assays (57.7 ± 4.2nm, Citrate-reduced, Quasi-spherical with dendritic protrusions) enable instrument-free, visual or smartphone-based readout of HPV-16/18, permitting quantitative results acquisition by untrained personnel without specialized equipmen (36). Carlos conjugated AuNPs (21.6 ± 0.1nm, Turkevich) with anti-HPV-16/18 L1 antibodies (37). Applied to 173 cervical samples, infection caused a color shift(red to purple) and LSPR red-shift (523~525 nm to 524~590 nm) (37). The assay detected HPV-16 L1 (linear range: 0.4~2.0μg/mL, LOD: 0.18μg/mL) and HPV-18 L1 (0.2~1.2μg/mL), identifying PCR-missed variants potentially via conserved L1 epitope recognition (37). To expand coverage, Jixue and team developed a multiplexed closed-tube PCR, detecting 17 HPV types (LOD: 0.5copies/μL, linear range: 0~1000copies/μL) with 99.05% accuracy (38).

Colorimetry lacks micro-scale sensitivity. Electrochemical biosensors convert biorecognition events to electrical signals (39). CEA, SCCA, Ki67, p53, and p16^INK4a are key cervical cancer biomarkers (35). Antibody-conjugated AuNPs enable their multiplexed detection. Electrochemical sensors universally use: 1) conductive substrates (Pt/Co/MoS₂/WS₂/rGO) to amplify AuNPs signals, and 2) engineered porous architectures (SiO₂ dendrimers, multilayered nanoparticles, 3D networks) to enhance target capture and conductivity ( Table 1 ) (40–42). These AuNPs-centered platforms show diagnostic promise (40). In a recent study, Hiranmoy et al. developed an ultrasensitive electrochemical immunosensor for cervical cancer biomarker p16^INK4a detection by modifying a glassy carbon electrode through sequential deposition of graphene oxide and ~70nm spherical AuNPs (43). The sensor utilized cysteamine-glutaraldehyde crosslinking to immobilize p16^INK4a monoclonal antibodies on the electrode surface (43). Compared to bare electrodes, Au/rGO-modified electrodes exhibited significantly enhanced peak currents with charge transfer resistance (Rct) reduced from 245 Ω to 14 Ω, demonstrating AuNPs’ capacity to facilitate electron transfer. Clinical serum analysis via square wave voltammetry achieved 100% accuracy with a detection limit of 167 fg/mL and linear range from 500 fg/mL to 100 ng/mL (43). The AuNP-engineered sensor demonstrated exceptional selectivity, storage stability, repeatability, reproducibility and regeneration capability.

Similarly, while colorimetry detects cervical exfoliated cells, its accuracy suffers from subjective visual interpretation of subtle color shifts. AuNP-integrated (~16nm, Citrate-reduced, Spherical, chitosan-coated) photoelectric sensors enhance precision by targeting cancer-specific α2,6-sialic acid overexpression via SNA-conjugated AuNPs (44). Ricardo and team detected diagnostic spectral alterations at 1470, 1456, 1434, 1400, and 1350 cm⁻¹ in cancer-bound complexes using attenuated total reflection fourier-transform infrared spectroscopy (ATR-FTIR) (44). Notably, Ricardo et al. leveraged machine learning (ML), specifically principal component analysis (PCA), to identify sialic acid-associated spectral signatures in cervical cancer cell lines. Orthogonal principal components maximizing data variance were derived, enabling construction of confidence ellipse models that robustly discriminated primary fibroblasts from malignant cells (non-overlapping 95% confidence intervals; p<0.001) (44). This approach establishes a non-invasive diagnostic paradigm for early cervical cancer detection through surface-enhanced infrared absorption (SEIRA) biomarker profiling. ( Figure 3 ).

AuNPs enhance HPV-16 DNA detection by increasing electrode surface area, accelerating electron transfer, and amplifying signals (39, 45). As Table 2 shows, varied electrode designs achieve LODs<0.2fM (46–49). Dielectric and photoelectrochemical sensors offer enhanced precision, with maintained functionality during long-term cold storage (46, 48).

Lin and colleagues’ paper-based sensor achieves significant cost reduction (<$1.00), miniaturization, and commercial viability (53). Utilizing lateral flow principles, HPV-16/18 DNA hybridizes with probes in a rapid-flow zone, forming circular structures that bind AuNPs (~40nm, Spherical)-polydopamine (PDA). Light irradiation triggers AuNP-mediated photothermal conversion, intensifying thermal response while diminishing photocurrent. Subsequent fluid migration to a slow-flow zone enables CRISPR-Cas12a-mediated DNA cleavage and HPV fragment release, reversing signals ( Figure 4 ) (53). This system detects HPV-16/18 DNA within 30 minutes with high specificity (LOD: 0.21pM and 42.92pM, respectively) (53). However, Lin’s sensor is susceptible to temperature, salt concentration, and reaction time variations due to pre-hybridization nucleic acid cleavage. These factors exacerbate electrical signal transduction limitations, including single-molecule counting inability. To overcome this, Jia and team integrated dark-field microscopy (DFM) imaging, circumventing signal dependency while employing synergistic sedimentation (SynSed) to minimize nanoparticle diffusion (~15nm, Citrate-reduced) (54). This optimized system achieves a LOD of 10 fM.

Beyond HPV-16 and HPV-18, other high-risk HPV types (31, 56, 59, 68) also contribute to cervical cancer development (35). To address this, platforms incorporating MY11 probes targeting conserved regions of the HPV L1 gene have been integrated with AuNPs-doped detection systems. AuNPs amplify current-voltammetric signals generated by minor nucleotide variations within the L1 conserved regions of HPV-16/31/33/45/58, enabling the construction of HPV genotyping profiles (51). Conversely, an alternative strategy anchors multiple recognition probes within a photoelectrochemical biochip array (PEBA) platform composed of TiO₂@AuNPs composites (52). This highly integrated chip-based format achieves an exceptionally low LOD of 0.1 copies/μL, demonstrating high concordance with clinical results (52).

SERS surpasses electrochemical biosensors in AuNPs-based serological diagnostics by circumventing electrode constraints. As Table 3 shows, platforms utilize: 1) sharpened AuNPs geometries to intensify electromagnetic hotspots, and 2) ordered array chips to enhance spectral reproducibility (55–58). However, significant LOD variability exists (e.g., 191.73 fM vs. 10 fM for SCCA in serum) (55, 58), likely stemming from AuNPs morphology and Raman reporter differences ( Figure 5 ).

SERS and Surface Plasmon Resonance Imaging (SPRi) are increasingly favored for cervical cancer biomarker detection ( Table 3 ). Yifan and team developed a dual-mode SPRi/SERS biosensor with a polyA capture probe/target miRNA/AuNPs-enhanced probe sandwich architecture (60). This platform concurrently detects miRNA-21/124/143 on a single chip (60). Target hybridization forms ternary complexes where AuNPs enhance SPRi via refractive index modulation while generating SERS hotspots through LSPR (60). Dual-signal redundancy reduces false positives (serum recovery: 90.0–100.2%) (60). This high-throughput platform provides dual-verified nucleic acid detection with clinical utility.

The spatial arrangement of AuNPs in SERS sensors critically determines analytical outcomes. Xingkang et al. engineered a nanoscale monolayer film of uniform AuNPs (83 ± 6nm) to generate evenly distributed dense hotspots, overcoming the random hotspot distribution characteristic of conventional plasmonic colloidal solutions (64). This design prevented heterogeneous electromagnetic signals arising from nanoparticle aggregation while enhancing SERS signal reproducibility and sensitivity (64). Furthermore, integration of CD63 nanoflares with AuNPs created supplemental hotspots that amplified SERS intensity by 4.1-fold (64). The resulting platform exhibited linear detection of cancer exosomes from 1×10⁶ to 2×10⁸ particles/mL with a limit of detection (LOD) of 4.7×10⁵ particles/mL (64).

Artificial intelligence enables more efficient mining of the massive data generated by AuNP probes in SERS sensing analysis, forming the foundation for low-cost nonspecific analysis. Hongmei and team established that 10 ppm serum prevents AuNPs encapsulation while enhancing dispersion homogeneity (63). After screening lasers, they selected 785 nm and 633 nm excitation (excluding 532 nm due to fluorescence interference), achieving 0.9609 spectral cosine similarity at 10 ppm (63). Clinical validation with 36 sera (24 healthy/12 cancer) identified differential peaks at 1201 cm⁻¹ and 1312 cm⁻¹. PCA achieved complete group separation, establishing the first standardized SERS reference library for cervical cancer sera. This methodology provides a robust foundation for clinical SERS translation (63).

Meanwhile, this simultaneously enables unsupervised recognition of cervical cell pathology through AI analysis of non-functionalized gold nanoparticles (nfGNPs). Karunakaran et al. implemented support vector machine (SVM) algorithms to achieve high-precision classification of NRML/HSIL/CSCC specimens (94% ± 0.73% accuracy for single-cell analysis), markedly improving post-PCA specificity with ROC-validated diagnostic progression (AUC >0.98) for cervical lesion stratification (61). In contrast, Diao et al. adopted a PCA-LDA fusion strategy (62). Following Savitzky-Golay filtering with airPLS background correction and min-max normalization, PCA reduced spectral dimensions to 46 principal components retaining 95% of the variance (62). LDA then compressed these into two discriminative factors. This hierarchical approach resolved non-overlapping 95% confidence ellipses observed under singular methods and attained 91.1% accuracy in differentiating exosomes across H8, HeLa, and MCF-7 cell lines (62). The model demonstrated robust diagnostic efficacy, with AUCs ranging from 0.93 to 0.99, and maintained 93.3% overall accuracy in clinical validation (62). It perfectly classified breast and cervical cancer serum exosomes while correctly identifying 80% of healthy samples. This established a non-invasive framework for SERS-driven early cancer detection (62).

Imaging is vital for non-invasive cervical cancer diagnosis. Tumor-targeting ligand-functionalized AuNPs (e.g., folic acid, oligotyrosine/RGD/NLS peptides) serve as effective contrast agents (65). The tumor microenvironment further enhances AuNPs (50.3 ± 1.1nm, Citrate-reduced, spherical) accumulation, where acidic pH triggers hydrolysis of citraconic anhydride linkages in AuNPs-doxorubicin (DOX) complexes (66).

Radioiodinated AuNPs serve as contrast agents for clinical imaging (MRI/US/CT/PET) (29). Min and colleagues engineered pH-responsive theranostic AuNPs (50.3 ± 1.1nm, Microwave-assisted synthesis, spherical) with PEGylated surfaces and citraconic anhydride-linked DOX (66). At pH 5.5, linker hydrolysis triggers DOX release and electrostatic aggregation (35-nm UV-Vis redshift; TEM-confirmed), amplifying imaging signals (66). Radioiodination achieved 35.4% labeling efficiency, with PET showing 1.37%ID/g tumor uptake at 2h and >38% cancer cell binding (66). Photoacoustic imaging (PAI) generates biological images by detecting photon emissions from contrast agents. AuNPs exhibit exceptional PAI properties due to high photothermal conversion efficiency (66). The Au-UCNP-PEG_2k nanocomposite serves as both photodynamic therapy agent and multimodal imaging platform (~5nm, Hydrothermal method, spherical) (67). In vivo studies show superior PAI performance under near-infrared region (NIR) irradiation compared to bare AuNPs, functioning as a trimodal contrast agent for comprehensive tumor diagnostics ( Figure 6 ) (67).

AuNPs enhance lesion identification in laboratory imaging (68). Under DFM, FA-targeted AuNPs@Ag@AgI nanostructures internalized by HeLa cells enable precise spatial localization via amplified light scattering (68). Simultaneously, AuNPs’ plasmonic properties mediate surface energy transfer to fluorescent donors (e.g., TAP, PHEN), inducing controlled fluorescence quenching within cells, supporting development of real-time imaging agents (68).

AuNPs enable targeted cancer cell eradication via drug and ligand conjugation. Therapeutic payloads encompass Methotrexate (MTX) (69), DOX (66), Paclitaxel (PTX) (70), and luteolin (71). Common cervical cancer targeting ligands comprise Folic Acid (FA), Hyaluronic Acid (HA), and AS1411 aptamer ( Table 4 ). Emerging agents show complementary potential (72). The investigational compound IQ activates TLR7/8-mediated immune responses and NF-κB-dependent apoptosis. When complexed with nucleolin-targeting AS1411 aptamer on AuNPs (IQ-AS1411-AuNPs), MTT assays demonstrated significantly reduced HeLa cell viability (72).

Beyond ligand-mediated targeting, tumor microenvironment (TME) characterized by hypoxia, low pH, elevated GSH, and ROS, directs AuNPs accumulation. A TME-responsive platform bypasses ligand functionalization, exemplified by GSH-cleavable disulfide-linked AuNPs (~11nm, Brust-Schiffrin, spherical) achieving 98.7% MTX encapsulation for cervical cancer (69). Similarly, DOX-conjugated AuNPs utilize pH-labile hydrazone bonds that hydrolyze selectively in acidic TME conditions, enabling clinically translatable targeted therapy (66, 73).

Toxicity and complexity concerns around chemical stabilizers (e.g., 3MPA/3MPS/PVP) drove Kamini et al. to develop a novel PTX delivery platform (70). Their method synthesizes PTX-AuNPs in one step by adding silver ions to PTX/gold ion suspensions under sunlight ( Figure 7 ), where PTX acts as both therapeutic payload and reducing/stabilizing agent (70). This eliminates pre-synthesized AuNPs and exogenous stabilizers, reducing costs while bypassing conventional drug-loading, though the photochemical mechanism requires further study (70).

AuNPs exert intrinsic cytotoxicity against cervical cancer cells via apoptosis modulation (72, 74). Concentration-dependent upregulation of pro-apoptotic markers (BAX, p53) and downregulation of anti-apoptotic factors (Bid, BCL-2) occur with concomitant caspase activation (75). This cascade initiates from AuNPs-induced intracellular ROS elevation, confirmed by flow cytometry showing increased cytoplasmic ROS and mitochondrial superoxide production (76). AuNPs generate ROS partly through intrinsic catalytic activity, converting H₂O₂ into H₂O and O₂ while enhancing catalase activity to modify the tumor microenvironment via hypoxia alleviation and immune potentiation (77). Additionally, AuNPs elevate superoxide dismutase (SOD) activity, causing H₂O₂ accumulation that activates caspase-dependent signaling pathways to induce cancer cell apoptosis (77). AuNPs’ cytotoxicity against cervical cancer cells depends critically on nanoparticle diameter and subcellular localization (78). Dae et al. found extracellular monodisperse AuNPs prolong HeLa cell mitosis without inducing apoptosis by forming division-disrupting nano-barriers. By contrast, 111nm extracellular AuNPs trigger ROS-mediated cell death with cytokinesis arrest, while 83nm particles cause transient M-phase delay followed by normal cytokinesis and G₁-phase entry (78).

AuNPs act as efficient photothermal transducers, enabling precise tumor ablation under targeted guidance (21). Recent refinements include S-nitrosothiol-modified AuNPs releasing nitric oxide during PTT to simultaneously soften tumor extracellular matrix and generate mitochondrial reactive nitrogen species for enhanced cytotoxicity (79). Multibranched gold nanocrystals further outperform spherical or rod-shaped counterparts in photothermal conversion efficiency, confirming morphology as critical design parameter (21). PDT employs photosensitizers to generate cytotoxic ROS but faces limitations including toxicity and poor cellular uptake. Armin and team further demonstrated that AuNPs functionalized with protoporphyrin IX and FA via mercaptohexanol linkers enhance both cancer selectivity and cytotoxic efficiency (80).

AuNPs enhance cervical cancer radiotherapy efficacy through their high atomic number (Z = 79), which dramatically exceeds biological elements. This promotes X-ray/γ-ray absorption, generating amplified secondary electron fluxes that directly damage tumor DNA (81). Radiation-activated gold nanorods (AuNPs, 54.6 ± 7.11nm, spherical) further catalyze water decomposition, producing cytotoxic ROS (82). Functionalized variants concentrate radiation energy within lesions. Radiosensitization varies significantly with geometry: AuNRs surpass spheres (83). Nanocubes deposit 18.5% (18 MV) to 23.1% (6 MV) higher electron doses than nanospheres within 1.1 µm radii, achieving maximum dose enhancement at 6 MV (84).

Colorimetry enables rapid ovarian cancer biomarker screening but suffers from limited resolution. Eda et al. circumvented this via smartphone-integrated analysis leveraging mobile imaging hardware advances (~40nm) (85). Alternatively, Hao et al. engineered Mg/Fe-layered double hydroxide nanoflowers as high-density AuNPs (~10nm, Rapid injection synthesis) carriers for lateral flow immunoassay (LFIA) (86). These porous templates achieve ultrahigh AuNPs loading, lowering HE4 detection to 50 pM (86).

CA125 is the clinical gold standard for ovarian cancer serology. Current AuNP-based detection platforms vary primarily in electrode composition and surface modification strategies( Table 5 ), integrating AuNPs with carbon nanomaterials (graphene, CNTs), polymers (chitosan, polydopamine, PAMAM), or novel frameworks (MXenes, MOFs) to enhance nanoparticle density, antigen capture efficiency, and electron transfer kinetics. The integration of MOFs with AuNPs achieves reproducible CA12-specific recognition, demonstrating a RSD of 2.98% in repeatability experiments (87). Zahra’s MXene/GQD/AuNPs composite achieves a record LOD of 0.075nU/mL (88). DLS sensors offer the broadest linear range (5fg/mL~50ng/mL) for high-dynamic CA125 quantification (89), while AuNP-DNA fluorescence quenching enables continuous biomarker monitoring. Near-field communication (NFC) integration further streamlines data acquisition, enhancing clinical utility (90).

Beyond CA125, AuNP-based sensors target biomarkers including p53, HE4, exosomes, and DNA methylation (91, 103–106). Following Weiwei et al.’ s MOF-AuNPs for CA125 (95), Xu and team developed a sandwich electrochemical immunosensor using synergistic signal amplification between Prussian blue (PB) and thiolated ionic MOF composites (TIMO⁺F-KB@AuNPs) for HE4 quantification (107). The platform employs TIMO⁺F-KB@AuNPs as conductive sensing substrates for capture antibody (Ab₁) immobilization, while PB nanoparticles carry detection antibodies (Ab₂). HE4 binding forms an Ab₁-HE4-Ab₂-PB complex, generating electrochemical signals proportional to concentration (linear range: 0.1~80ng/mL, LOD: 0.02ng/mL) (107). Demonstrating high selectivity, reproducibility, and stability with 97.10~114.07% serum recovery, it enables early ovarian cancer diagnosis ( Figure 8 ). Separately, superparamagnetic CoFeB enhances AuNPs-based p53 detection (LOD: 0.006 U/mL) (104). Furthermore, exosomes predict ovarian cancer chemotherapy response. Meshach and team developed a cysteine-functionalized AuNP (Au-cys) biosensor using SERS to simultaneously capture cisplatin and small extracellular vesicles from biological samples, enabling concurrent early detection and treatment efficacy assessment (102).

AuNPs facilitate ovarian cancer diagnosis via urine, exhaled gas, and cyst fluid analysis (108, 109). Thomas and team pioneered nanopore sensing where AuNPs capture 13 cysteine-containing urinary peptides within α-hemolysin nanopores, generating distinct current signatures: stepwise reductions for small peptides versus polymorphic fluctuations for larger ones, enabling prolonged single-molecule characterization (108). AuNPs-based platforms also detect microbiome-derived Volatile organic compounds (VOCs) in exhaled breath with 82% screening accuracy (110).

AuNPs drive transformative ovarian cancer imaging advances (19). Dheeraj and team engineered FA-targeted, hydrazinonicotinamide-chelated AuNPs enabling efficient 99mTc radiolabeling for tumor-specific single-photon emission computed tomography (SPECT) contrast (111). Further functionalization yielded GO/SPIO/AuNP composite sheets integrating PTT, radiotherapy, and MRI within a unified theranostic platform (112).

MARS spectral photon-counting CT (SPCCT), though primarily preclinical, enables material-specific imaging via energy-dependent X-ray attenuation. Dhiraj et al. functionalized AuNPs with LHRH via PEG tethers for ovarian cancer targeting (113). Intraperitoneal administration in murine models achieved selective accumulation in peritoneal tumors (0.46~2.12ng/mg, ICP-MS). While current SPCCT sensitivity limited absolute quantification, it mapped gold distribution patterns (113). Increased LHRH density (3000~15000molecules/particle) enhanced targeting while maintaining >60% metabolic activity at therapeutic concentrations (12~30μg/mL), establishing a novel theranostic strategy (113).

Functionalized AuNPs support ovarian cancer-specific detection via fluorescence lifetime imaging (114), dark-field (115), and confocal Raman microscopy (116). SERS imaging further enables chemoresistance prediction and survival outcome assessment (117).

AuNPs enable targeted ovarian cancer drug delivery, enhancing dispersion or internalization of agents like linalool, cetuximab, paclitaxel, let-7a miRNA, and nidocarcinoma-derived factor( Table 6 ). DOX-AuNPs show superior tumor growth inhibition versus free doxorubicin while overcoming payload leakage limitations (118). Engineered for MICU1-targeting siRNA delivery, they achieve >85% silencing efficiency via lysosome evasion, addressing key shortcomings of conventional carriers (119).

Antibody or peptide-conjugated AuNPs enable precise ovarian cancer targeting (128). Edison and team engineered FSH33-AuNPs covalently conjugated to tumor-suppressive miR-145 (122). This system protects miR-145 from degradation, mediates selective cancer cell internalization, and inhibits proliferation, migration, anchorage-independent growth, and VEGF secretion. AuNPs enable co-delivery of multiple therapeutic agents, as demonstrated by Tommaso et al. who engineered miR-200c and trastuzumab (TZ)-loaded nanoparticles that dual-target critical pathways driving SKOV3 cell survival and proliferation in vitro, overcoming TZ resistance while potentially improving therapeutic outcomes for HER2-positive ovarian cancer (126). Beyond antibody/peptide targeting, TME and hyperthermia trigger drug release from AuNPs^,123. Reza et al. engineered antibody-conjugated magneto-gold composites (TXT@Fe₃O₄/PVA/Au-SORT) for ovarian cancer (28). Photothermal AuNPs heating dissociates the PVA matrix, achieving precise TXT release (94.4 ± 4.1% over 180 min in TME). Ca(OH)₂ pretreatment combined with TXT therapy enhanced intratumoral accumulation, inhibited migration, and induced DNA damage, achieving 78.3% tumor suppression with reduced systemic toxicity ( Figure 9 ).

Notably, AuNPs morphology critically influences therapeutic outcomes: anisotropic AuNPs@CSA-131 exhibit enhanced cytotoxicity against ovarian carcinoma versus spherical counterparts (124). Furthermore, AuNPs modulate drug presentation in vivo, facilitating theaflavin oxidation to cytotoxic quinone derivatives (125). Regarding therapeutic side effects, The triple-modality approach (ultrasound/AuNCs/cisplatin) overcomes cisplatin resistance in resistant ovarian cancer models, suggesting reduced chemotherapy side effects with translational potential (129).

AuNPs inhibit ovarian carcinoma invasiveness by targeting key oncogenic pathways: impeding MAPK signaling, suppressing EMT-associated proteins, and disrupting the IGFBP2/mTOR/PTEN autoregulatory axis, downregulating IGFBP2, suppressing PI3K/AKT/mTOR activation, and reactivating PTEN (130, 131). Current understanding posits that AuNPs disrupt multicellular TME communication (cancer cells, cancer-associated fibroblasts, endothelial cells), downregulating pro-tumorigenic cytokines and growth factors (132, 133). Specifically, they reduce CC-secreted fibroblast-activating proteins (TGF-β1, PDGF, uPA, TSP1) and inhibit tumor angiogenesis by blocking VEGF-VEGFR2 signalling (133, 134). This positions AuNPs as key tools for elucidating and disrupting pro-tumorigenic crosstalk. AuNPs synchronize disulfidptosis and ferroptosis in ovarian cancer by modulating the SLC7A11/GSH/GPX4 axis (135). The composite system exploits AuNPs’ glucose oxidase-like activity and Ap-mediated GLUT1 downregulation to induce metabolic crisis (135). Glucose deprivation limits NADPH replenishment, disrupting cystine/cysteine conversion and resolving the disulfidptosis-ferroptosis execution paradox. Concurrently, iron-based components deliver Fe²⁺ while AuNPs-catalyzed glucose oxidation self-supplies H₂O₂, amplifying Fenton reactions and ferroptotic death (135).

Beyond influencing signalling pathways, AuNPs enhance nuclear rigidity via perinuclear laminA/C overexpression, impeding cancer cell migration (136). Concurrently, they induce ROS-mediated apoptosis/autophagy, trapping cells in G0/G1 phase (137). Anisotropic AuNPs exert enhanced anti-migratory effects versus spherical counterparts (138). Analogous to cervical cancer applications, morphological engineering of AuNPs enhances their cytotoxic efficacy against ovarian cancer cells. Irfan et al. attribute this phenomenon to elongated-branched antibody-functionalized AuNPs effectively evading serum protein corona entrapment, thereby facilitating optimal aptamer binding to HER2 receptors on cancer cell surfaces (139). This mechanism induces significant cytotoxicity in HER2-overexpressing SKOV3 cells through targeted apoptosis initiation.

AuNPs enable synergistic chemo-photothermal therapy for ovarian cancer (127, 140). Yiting et al. engineered a genetically fused HSA nanocarrier (RHMH18@AuD) self-assembling via histidine hydrophobicity to encapsulate DTX while forming ultrasmall AuNPs through biomimetic mineralization (141). This 80-nm platform prevents HSA denaturation and reduces inorganic nanoparticle toxicity. MMP-2 cleavage at tumors releases RGD-HSA@Au (mediating photothermia) and His@DTX micelles, with acidic TME-triggered DTX release. The system demonstrated targeted cellular uptake, significant tumor suppression, and 100% survival at 70 days versus complete mortality in monotherapy groups by day 62, establishing a high-efficacy, low-toxicity therapeutic strategy.

Diverse AuNPs composites serve as photothermal agents for ovarian cancer PTT. rGO-AuNPs-PEG exhibits strong SERS signals, NIR-II PA signals, and high photothermal efficiency in tumours under 1061 nm laser irradiation (142). Similarly, silica nanocapsules containing aggregated AuNPs yolk-shell structures (aAuYS) demonstrate enhanced photothermal effects with 808 nm laser exposure (143). Curcumin-incorporated gold nanoshells (Cur-AuNShs) show efficient photothermal conversion with potential for selective cancer targeting and treatment. Additionally, AuNPs morphology influences PTT efficiency (144). For instance, dumbbell-shaped Au-Fe₃O₄ elevate thermal conversion efficacy (145).

To overcome resolution limitations in image-guided PTT, Annan et al. developed ultra-small GnRHR-targeted AuNDs (Au-GRHa, 3.2nm) (146). Prepared via electrochemical displacement and ligand conjugation, these nanoconstructs enable dual-modal fluorescence/CT imaging with superior CT contrast (attenuation coefficient: 5.153cm²/g) and renal clearance. GnRHa targeting boosted SKOV3 cellular uptake by 76% versus non-targeted counterparts. Under 808 nm irradiation, localized temperatures reached 50 °C within 5 min, inducing apoptosis via membrane disruption and protein denaturation. In vivo peak tumor accumulation occurred at 2 h, with subsequent PTT significantly suppressing tumor growth without hemolysis or toxicity, establishing a precise image-guided therapeutic platform.

PDT and PTT act synergistically against ovarian cancer. A multifunctional nanomicrogel (Au@MSN–Ter/THPP@CM@GelMA/CAT) demonstrates concurrent photodynamic efficacy (650nm) and photothermal ablation (980nm) (147).

AuNPs exhibit radiosensitizing effects, exemplified by thioglucose-bound nanoparticles (Glu-GNPs) enhancing ovarian cancer radiotherapy (148). The GO-SPIO-Au nanoflower platform integrates graphene oxide (NIR-PTT), AuNPs (radiosensitization), and superparamagnetic iron oxide (MRI) for image-guided therapy (112). In murine models, combined PTT/RT yielded 1.85× and 1.44× higher efficacy than PTT or RT alone, respectively. Kinga et al. developed a novel cancer therapy combining antibody-drug conjugates (ADCs) with β-emitting ¹⁹⁸AuNPs conjugated to trastuzumab emtansine (T-DM1), demonstrating specific HER2 affinity and synergistic efficacy against HER2-overexpressing cancers at low T-DM1 doses (0.015~0.124μg/mL) with 10–20 MBq/mL radiation (149). Continuous 7-day treatment (20 MBq/mL+0.031μg/mL T-DM1) disrupted 3D tumor spheroids, suggesting potential for HER2-positive breast/ovarian cancer treatment despite preferential suitability of inorganic nanoradiopharmaceuticals for localized delivery ( Figure 10 ) (149).