Multifunctional gold nanoparticles: bridging detection, diagnosis, and targeted therapy in cancer

Abstract

Cancer remains a leading global health challenge, responsible for millions of deaths annually. Conventional therapies are hindered by systemic toxicity, drug resistance, and ineffective targeting of the tumor microenvironment (TME). Gold nanoparticles (AuNPs) have emerged as promising tools in oncology, offering unique plasmonic properties, high biocompatibility, and the ability to be engineered for multifunctional applications. Recent advancements include sustainable biogenic synthesis methods, precision targeting through ligands, aptamers, and peptides, and the development of theranostic platforms that integrate multimodal imaging with controlled drug and gene delivery. Additionally, AuNPs are being combined with therapies like photothermal-immunotherapy to remodel the TME, enhancing therapeutic efficacy. This review explores AuNP applications in cancer detection, diagnosis, and therapy, focusing on targeted drug/gene delivery to overcome chemoresistance, advanced biosensing tools for early detection, hybrid nanocarrier designs for TME penetration, and combinatorial platforms for integrating photodynamic, chemotherapy, and radiotherapy. It also addresses key translational barriers, such as protein corona dynamics, long-term biodistribution concerns, and the scalability of green synthesis methods. To facilitate clinical adoption, it emphasizes the need for GMP-compatible manufacturing, personalized nanomedicine through computational design, and standardized safety assessments. AuNPs represent a transformative approach to precision oncology, with the potential to integrate diagnostic and therapeutic functions into adaptable, real-time systems.

Graphic abstract

Introduction

Cancer remains a global health challenge and one of the leading causes of death worldwide, which is characterized by its molecular complexity, heterogeneity, and dynamic evolution, presenting significant hurdles in both diagnosis and treatment [1–3]. Despite substantial advancements in conventional therapies, such as surgery, chemotherapy, and immunotherapy, the clinical outcomes for many cancer patients remain unsatisfactory [4–8]. These therapies often come with significant limitations, including systemic toxicity, drug resistance, and the inability to effectively target and disrupt the tumor microenvironment (TME) [9–12]. The TME itself, comprising a dense extracellular matrix (ECM), stromal cells, and immune suppressive signaling networks, presents a formidable barrier to effective drug delivery and therapeutic efficacy, making it a key area of focus in cancer research [13].

The intricate nature of the tumor microenvironment (TME) contributes significantly to the limitations of many conventional cancer treatments, hindering therapeutic agents from effectively reaching tumor cells. Beyond creating a physical barrier, the TME actively fuels tumor survival and progression. It shields cancer cells from immune attack, stimulates the growth of new blood vessels for tumor nourishment (angiogenesis), and facilitates the deadly spread of cancer to distant sites (metastasis) [14–17]. Consequently, the field increasingly recognizes that solely directing therapies at the cancer cells themselves falls short. Successfully combating cancer requires strategies that simultaneously attack both the tumor and its supportive microenvironment. This understanding drives ongoing efforts to develop new therapeutic approaches offering greater specificity, deeper penetration into tumors, and overall enhanced effectiveness [18, 19].

Nanotechnology represents a highly active frontier in this pursuit. Engineered nanoparticles, leveraging their minute size, tunable optical properties, and capacity for precise functional design, provide powerful tools to tackle hurdles intrinsic to traditional cancer therapies [4, 20–22]. Nanoparticle-based delivery systems overcome critical biological barriers—including intracellular delivery via endocytic pathways, trans-epithelial translocation across mucosal/blood-brain barriers, tumor microenvironment infiltration leveraging the EPR effect, and immune cell targeting through receptor-specific uptake-enabling precision therapeutic delivery (Fig. 1). Among these, gold nanoparticles (AuNPs) stand out in cancer research. Their excellent biocompatibility, straightforward surface modification, and distinctive physicochemical properties—including strong light absorption—position them as exceptionally promising platforms for targeted drug delivery, advanced imaging, and novel therapeutic interventions [23–26].

Fig. 1.

Biological barriers overcome by nanoparticle-based delivery systems. Nanoparticles facilitate targeted therapeutic delivery by overcoming key physiological barriers, including: (1) Intracellular Delivery: Enhanced cellular uptake via endocytic pathways and endosomal escape mechanisms; (2) Trans-Epithelial Barrier Delivery: Improved translocation across mucosal/epithelial linings (e.g., gastrointestinal tract, blood-brain barrier) through transcytosis and paracellular transport modulation; (3) Tumor Microenvironment (TME) Penetration: Enhanced permeation through dysfunctional tumor vasculature (EPR effect) and stromal matrix to reach malignant cells; (4) Immune Cell Targeting: Selective delivery to antigen-presenting cells (APCs) and lymphocytes via surface receptor-mediated uptake, enabling precision immunomodulation. Created by Biorender.com

The true power of AuNPs lies in their tailorability. Scientists can precisely control key characteristics like surface charge, size, and surface chemistry (functional groups). This precise engineering is fundamental for achieving targeted delivery of therapeutic payloads specifically to tumors [27–29]. This field, termed nanomedicine, envisions a transformative shift in cancer care towards regimens that are far more targeted and adaptable to the individual patient [30, 31]. Furthermore, AuNPs uniquely enable combination therapies. A single nanoplatform can integrate multiple treatment modalities—such as photothermal therapy (PTT), photodynamic therapy (PDT), and gene therapy—thereby boosting treatment efficacy and tackling persistent problems like drug resistance and metastasis [32–37].

Recent progress in environmentally conscious “green synthesis” methods further bolsters AuNP potential. This approach utilizes plant extracts, fungi, or microbes instead of harsh chemicals to produce AuNPs [38, 39]. Beyond offering a sustainable and scalable manufacturing route, green synthesis often imparts additional bioactive properties derived from the natural source material. Plant-derived AuNPs, for instance, sometimes demonstrate inherent anticancer activity, adding an extra layer to their therapeutic capability [40, 41]. Combining green-synthesized AuNPs with established anticancer drugs presents a dual benefit: reduced environmental impact from nanoparticle production paired with maintained, or potentially amplified, therapeutic outcomes [42].

This review critically assesses the latest progress in AuNP-based technologies for cancer diagnosis, treatment, and combined theranostics. We will explore the defining characteristics of AuNPs, detail their diverse applications across therapeutic and diagnostic strategies, and confront the key challenges that must be navigated for successful translation into clinical practice.

AuNPs in cancer therapy

Cancer continues to rank among the most pressing global health issues. Its inherent complexity and heterogeneity severely hamper effective treatment strategies. While conventional approaches—chemotherapy, radiotherapy, and immunotherapy—have demonstrably improved care for many patients, significant limitations persist. These include severe systemic toxicity, the development of treatment resistance, and the fundamental challenge of selectively destroying tumor cells without damaging surrounding healthy tissue. To overcome these hurdles, nanotechnology—specifically biogenic gold nanoparticles (AuNPs)—provides a promising strategyy [43, 44]. The minute size, inherent biocompatibility, and capacity for precise functionalization of AuNPs equip them exceptionally well for targeted drug delivery and enhanced cancer treatment [45–48].

Biogenic AuNPs for targeted cancer therapy: Harnessing plant, fungal, and microbial systems

Biogenic synthesis represents a paradigm shift in AuNPs production, leveraging sustainable plant, fungal, and microbial systems to generate eco-friendly nanotherapeutics. This approach not only eliminates toxic reagents but also imbues AuNPs with inherent bioactivity and enhanced tumor targeting capabilities. We critically examine plant-derived systems for their phytochemical synergy, fungal routes enabling high-yield biocompatible probes, and microbial platforms optimizing therapeutic efficacy. Furthermore, innovative functionalization strategies-including hybrid nanocomposites and stimuli-responsive carriers—are explored to overcome drug resistance and maximize precision oncology applications. The biogenic synthesis and functional optimization of AuNPs for targeted cancer therapy was showed in Table 1.

Table 1.

Biogenic synthesis and functional optimization of AuNPs for targeted cancer therapy

Synthesis Method	Reducing/Stabilizing Agent	Nanoparticle Characteristics	Biocompatibility Assessment	Therapeutic Application	Impact on Tumor Type	Key Findings	References
Green synthesis using Borassus flabellifer (palm candy) fruit extract	Palm candy extract	Drug-loaded (5-FU), cytotoxic to pancreatic cancer cells	Not explicitly stated	Pancreatic cancer	Pancreatic cancer (MiaPaCa-2): Enhanced cytotoxicity and apoptosis compared to free 5-FU.	Superior tumor suppression via targeted drug delivery.	[53]
Green synthesis using Ganoderma mushroom mycelial extract	Ganoderma mycelium extract	Monodisperse, spherical, 20 nm, water-soluble	Non-toxic to MDA-MB-231 breast cancer cells	Diagnostic/therapeutic applications	Breast cancer (MDA-MB-231): No direct cytotoxicity observed; biocompatible for future therapeutic use.	Biocompatibility confirmed; potential as a carrier for tumor-targeted imaging/therapy.	[56]
Green synthesis using CR (Madagascar periwinkle) plant extract	CR extract	25–35 nm, spherical	Selective cytotoxicity to HeLa cells	Cervical cancer	Cervical cancer (HeLa): Induced mitochondrial-mediated apoptosis via ROS generation.	ROS-dependent apoptosis confirmed; potential for theranostic applications.	[54]
Yeast-mediated synthesis combined with gold nanospheres	Saccharomyces cerevisiae (baker’s yeast)	Not specified	Safe for liver/kidney function in rat models	Breast cancer	Breast cancer (rat model): Reduced tumor growth via apoptosis induction (Bcl-2, Bax/caspases).	Tumor volume reduction; normalized liver function markers (ALT/AST).	[58]
Green synthesis of drug-loaded (curcumin/DOX) AuNPs via non-covalent binding	Plant extracts (unspecified)	Drug-loaded, ultrasound-responsive release	Effective against breast cancer cells	Breast cancer	Breast cancer: LIPUS-triggered drug release reduced cell viability.	Ultrasound-responsive release validated in vitro; synergistic therapeutic effect.	[61]
Garlic phytochemical-functionalized AuNPs	Garlic (Allium sativum) extract	Anti-proliferative, microtubule-targeting	Non-toxic to normal cells (L929, HeLa)	TNBC	TNBC (MDA-MB-231): Inhibited migration and clonogenicity via microtubule interaction.	No cell cycle arrest; selective targeting of microtubule dynamics in TNBC.	[60]
Green synthesis using Curcuma caesia (black turmeric) rhizome extract	Black turmeric extract	Selective cytotoxicity to TNBC cells	Non-toxic to normal cells (L929, HeLa)	TNBC and ER + breast cancer	TNBC (MDA-MB-231): IC50 = 5.87 µg/mL; ER+ (MCF-7): IC50 = 6.44 µg/mL.	TNBC-selective cytotoxicity demonstrated; minimal effect on normal cells.	[55]
Fungal-mediated biosynthesis for SERS applications	Filamentous fungi (e.g., Trichoderma)	Spherical/quasi-spherical, size/shape varies by fungal species	Not explicitly stated	SERS-based biosensors	N/A (Diagnostic application)	Fungal species-dependent SERS enhancement for methylene blue detection (enhancement factor: 20.9–35.46).	[57]
Green synthesis of curcumin-wrapped AuNP-graphene nanocomposite (CAG)	Curcumin	Composite structure (AuNP-graphene-curcumin)	Biocompatible with normal colon/liver cells	Colon cancer	Colon cancer: Selective cytotoxicity to cancer cells; spared normal cells.	Antioxidant activity enhanced; biocompatibility validated in normal colon (CCD-18Co) and liver (HL-7702) cells.	[59]

Green synthesis refers to the environmentally friendly production of nanoparticles using natural resources, such as plant extracts, fungi, and microorganisms [49, 50]. This approach not only reduces the use of toxic chemicals but also enhances the biocompatibility and potential therapeutic properties of the resulting nanoparticles. Figure 2 illustrates the green synthesis workflow: Biological sources (plant/microbial) are extracted, followed by magnetic stirring-assisted nanoparticle synthesis and physicochemical characterization. Among the various biogenic sources, plant-based systems have garnered significant attention due to their accessibility, cost-effectiveness, and the additional bioactive compounds that can be incorporated into the nanoparticles [51, 52]. For example, juice from Borassus flabellifer was utilized to synthesize 5-fluorouracil (5-FU)-loaded AuNPs (5FU-G-AuNPs), which demonstrated enhanced cytotoxicity in pancreatic cancer cells. These nanoparticles achieved a drug encapsulation efficiency exceeding 95% and selectively induced apoptosis, suggesting their potential for more effective and targeted chemotherapy [53]. Similarly, extracts from Catharanthus roseus (CR) were employed to synthesize CR-AuNPs, which triggered mitochondrial-dependent apoptosis in HeLa cervical cancer cells through reactive oxygen species (ROS) generation. The IC50 value of CR-AuNPs was found to be 50% lower than that of conventional chemotherapies, highlighting their enhanced therapeutic efficacy [54] (Fig. 3A). Furthermore, Curcuma caesia-derived AuNPs exhibited selective cytotoxicity towards triple-negative breast cancer (TNBC) cells, with an IC50 of 5.87 µg/mL in MDA-MB-231 cells compared to 6.44 µg/mL in MCF-7 cells. This selective targeting of aggressive cancer cells underscores the promising therapeutic potential of AuNPs for treating difficult-to-target cancers like TNBC [55].

Fig. 2.

Green synthesis workflow for nanoparticles. Schematic representation of the sustainable biosynthesis pipeline: (1) Biological source extraction utilizing plant phytochemicals or microbial metabolites; (2) Reaction synthesis involving magnetic stirring-assisted reduction/precipitation in aqueous media; (3) Nanostructure characterization via physicochemical analyses. This eco-friendly approach eliminates harsh reductants while enabling precise biomolecular capping

Fig. 3.

Exploitation of biogenic gold nanoparticles for precision oncology: leveraging phytogenic, mycogenic, and microbial systems. A Schematic illustration of cellular modulation triggered by CR-AuNPs in human cervical carcinoma (HeLa) cells. Reproduced with permission [54]. Copyright from Taylor & Francis Group, 2019. CR-AuNPs at concentrations of 5 and 10 mg/ml provoked a dose-dependent increase in ROS levels within HeLa cells. The induction of autophagy by CR-AuNPs appears to be correlated with the disintegration and/or fragmentation of megakaryocytes in HeLa cells, contingent upon the ROS levels produced. While high concentrations of CR-AuNPs (10 mg/ml) elicited autophagic apoptosis, lower concentrations (5 mg/ml) did not exhibit any antiproliferative or cytotoxic effects on HeLa cells. The principal signaling pathway involved in CR-AuNP-induced apoptosis in cervical carcinoma HeLa cells. B CAG nanocomposite synthesis illustration. Reproduced with permission [59]. Copyright from Public Library of Science, 2019. C Schematic diagram of the synthesis process for curcumin or doxorubicin-incorporated gold nanoparticles. Reproduced with permission [61]. Copyright from Springer Nature, 2024. a Complexation of curcumin or doxorubicin with gold ions followed by reduction of the gold ion complex using trisodium citrate, leading to the formation of gold nuclei. b Enlargement of gold nuclei through the adsorption of additional gold-drug complex molecules onto the nuclei surfaces, succeeded by further reduction and growth mediated by trisodium citrate, culminating in the formation of spherical nanoparticles embedded with anti-cancer agents

While plant-based synthesis is prominent, fungal and microbial routes are proving equally capable of generating biocompatible AuNPs. Fungal synthesis, for example, often yields nanoparticles with high efficiency, consistent size distribution, and excellent biocompatibility—properties highly desirable for both therapy and diagnostics [56]. Ganoderma species-derived AuNPs illustrate this well; synthesized as monodisperse, water-soluble particles, they exhibited no toxicity in MDA-MB-231 cells, making them promising for diagnostic imaging applications [56]. This inherent biocompatibility is crucial for safe use in clinical settings. Filamentous fungi like Trichoderma atroviride and Alternaria sp. can produce AuNPs whose size governs their surface-enhanced Raman scattering (SERS) properties, significantly boosting their utility for sensitive cancer imaging and molecular detection [57]. Similarly, yeast systems hold therapeutic promise. Gold nanospheres derived from Saccharomyces cerevisiae triggered programmed cell death (apoptosis) in rat mammary tumor cells by regulating key apoptotic proteins and effectively restored normal liver enzyme levels, indicating good safety and therapeutic potential [58].

Despite these encouraging advances with biogenic AuNPs, boosting their therapeutic efficacy and tumor specificity remains critical, especially to counter drug resistance and off-target effects. Researchers are now combining AuNPs with natural compounds or other nanomaterials to create more potent and selective hybrid nanocomposites. For instance, a one-pot synthesis produced curcumin-graphene-AuNP hybrids (CAG). These selectively killed colon cancer cells while sparing normal cells, leveraging the synergistic antioxidant and pro-apoptotic actions of the components to achieve targeted anticancer effects [59] (Fig. 3B). In another approach, AuNPs functionalized with garlic phytochemicals specifically disrupted microtubule dynamics in TNBC cells. This inhibited cell migration and colony formation without arresting the cell cycle, reinforcing their potential for treating aggressive cancers like TNBC where minimizing harm to healthy tissue is essential [60].

A key strength of nanomedicine is the potential to finely control drug release using external triggers. Stimuli-responsive delivery systems, including those based on plant-stabilized AuNPs, represent a valuable strategy to enhance cancer treatment precision and effectiveness. Such systems allow chemotherapeutic agents to be released only under specific tumor conditions, minimizing collateral damage to healthy tissues and improving overall therapeutic outcomes. For example, turmeric/DOX-loaded AuNPs were synthesized using non-covalent interactions and demonstrated ultrasound-triggered drug release under low-intensity pulsed ultrasound (LIPUS). This controlled release reduced breast cancer cell viability by over 70% in 3D tumor models, illustrating the potential of stimuli-responsive AuNPs in improving the efficacy of cancer therapies [61] (Fig. 3C).

AuNPs in targeted cancer therapy: advanced drug delivery strategies

Advanced ligand-functionalized AuNPs exemplify the evolution of precision oncology, utilizing tumor-specific receptors to achieve targeted drug delivery with minimized off-systemic toxicity [62, 63]. Beyond conventional ligands, emerging aptamer and peptide conjugates demonstrate superior tumor penetration depth and spatial control for co-delivering chemotherapeutic-genetic payloads [64–66]. We further explore combinatorial strategies including dual-drug encapsulation systems and stimuli-responsive nanoplatforms that exploit TME cues for controlled release. Theranostic integrations are highlighted, where real-time imaging-guided therapies synergize with immune-modulatory functions to overcome treatment resistance. Multifunctional AuNPs for targeted cancer therapy: advanced delivery and smart theranostics was displayed in Table 2.

Table 2.

Multifunctional AuNPs for targeted cancer therapy: advanced delivery and smart theranostics

Targeting Strategy	Drug/Ligand	Carrier System	Tumor Type	Key Mechanism	Main Outcomes	References
Folate receptor targeting	DOX	FA-conjugated PEGylated AuNPs	PCa	High encapsulation (96%), pH-dependent release	Enhanced cytotoxicity against PC3 cells in vitro.	[68]
EGFR antibody conjugation	Docetaxel (DTX)	DTX-Au-PEG NPs with anti-EGFR mAb	NSCLC (Lung cancer)	Active targeting via EGFR; DTX protection in Au core	Improved therapeutic index in 3D tumor models.	[69]
AS1411/FOXM1 aptamer co-targeting	DOX, FOXM1 aptamer	Chitosan-AuNPs loaded with AS1411/FOXM1 aptamers	Breast cancer (A549, 4T1)	Receptor-mediated endocytosis in target cells	Higher tumor suppression in vivo; reduced off-target distribution.	[71]
HER2-targeted DNA-hybridized AuNPs	FUdR, DOX	FUdR-DNA/AuNPs with DOX intercalation	HER2+ Breast cancer	Synergistic apoptosis via FUdR/DOX co-delivery	Enhanced cytotoxicity vs. free drug mixtures.	[74]
ASGPR-mediated targeting	DOX	Pectin-coated AuNPs (PEC-AuNPs)	Hepatocellular carcinoma	ASGPR-mediated endocytosis in HepG2 cells	Higher cytotoxicity in HepG2 vs. free DOX; pH/electrolyte stability.	[76]
Folate receptor targeting	Docetaxel (Dtx)	FA-conjugated AuNPs (AuNPs-Dtx-FA)	Lung cancer (H520)	Enhanced binding specificity	Superior cytotoxicity in H520 cells; potential for targeted delivery.	[200]
Folate-mediated ER/PR- tumor selectivity	Curcumin	FA-CurAu-PVP NPs	ER/PR- Breast cancer	Selective cytotoxicity in ER/PR- cells; anti-migration	High antitumor efficacy in vivo; no normal cell toxicity.	[201]
CD133 antibody targeting	5-FU	PEGylated AuNPs with anti-CD133 mAb	Colon cancer (HCT116)	CD133-mediated endocytosis	Significant reduction in HCT116 cell viability vs. non-targeted NPs.	[202]
Folate/EPR dual targeting	Methotrexate (MTX)	Ultra-small AuNPs (≤ 10 nm) conjugated with MTX	Breast cancer	Active (folate receptor) and passive (EPR) targeting	Improved efficacy and reduced toxicity in vivo vs. free MTX.	[203]
pH-responsive release	MTX	AuNP-MTX conjugate	Lung (A-549) & Colon (HTC-116)	Faster MTX release at acidic pH	Higher cytotoxicity vs. free MTX.	[204]
AS1411 aptamer targeting	DOX	PEI-g-PEG-AuNPs with AS1411 aptamer	Pan-cancer	Aptamer-mediated targeting; stable NPs (ζ = −29.3 mV)	Effective cancer cell killing in vitro.	[205]
PVP-stabilized ROS induction	DOX	DOX@PVP-AuNPs	Lung cancer	ROS generation, mitochondrial membrane sensitization	Upregulated tumor suppressor genes; superior growth inhibition vs. free DOX.	[206]
PSMA antibody (D2B) targeting	N/A (Carrier)	D2B-functionalized AuNPs (AuNPs-D2B)	PCa (PC-3)	PSMA-mediated binding; low cytotoxicity	Specific binding to PSMA+ cells; favorable properties for targeted therapy.	[207]
GB3 receptor targeting via Shiga toxin B	N/A (Photothermal agent)	ShTxB-functionalized AuNRs	Oral squamous cell carcinoma	GB3 receptor-mediated internalization	Selective photothermal killing in preclinical models; no pre-activation toxicity.	[208]
RBC membrane & PEI dual functionalization	Acridine orange (AO)	PEI/RBC membrane-coated AuMSS nanorods	Cervical cancer	Enhanced colloidal stability	Complete tumor elimination via chemo-PTT.	[77]
Folate-BSA protein corona	EGFP/RNase A	BSAFA-coated AuNRs (AuNR@EGFP/RNase A-BSAFA)	Colon cancer (HT29)	Receptor-mediated endocytosis; cytoplasmic protein delivery	Effective RNA degradation and cell death in 3D spheroids.	[78]
NIR-II triggered photothermal release	Melphalan (MPH), Curcumin (CUR)	β-CD-NS/AuNR complexes	Pan-cancer	NIR-II light (1064 nm)-triggered release	Controlled drug release; reduced cytotoxicity vs. free drugs.	[75]
PD-L1 inhibitor screening	Irinotecan	Ag/Au NPs conjugated with Irinotecan	Lung cancer (A549)	High PD-L1 binding affinity	Higher cytotoxicity in A549 vs. other drug-NP conjugates.	[80]
β-CD/HA/Chitosan composite targeting	Tamoxifen citrate	β-CD-HA-Chitosan-Au nanocomposite	Colon (Caco-2) & Breast (MCF-7)	Enhanced uptake via HA-CD44 interaction	Reduced IC50 (5.32 µM in Caco-2) vs. free drug (8.55 µM).	[67]
PEGylated iron oxide-AuNPs	Rapamycin	R-Au-IONPs (PEGylated Au-coated iron oxide NPs)	Breast cancer (MCF-7)	Controlled release; apoptosis induction	Significant cytotoxicity and apoptosis in MCF-7 cells.	[209]
LINC01615 suppression	Lapatinib	LPT-CS-AuNPs (Chitosan-AuNPs)	Lung cancer	Downregulation of LINC01615 RNA; apoptosis enhancement	Reduced LINC01615 expression and enhanced apoptosis.	[210]
Mitochondrial targeting with TPP	DOX	Dox@TPAu (Virus-like AuNPs with TPP)	Pancreatic cancer	Disruption of mitochondrial function	Synergistic chemo-PTT; ECM depletion.	[211]
iRGD-mediated tumor penetration	Paclitaxel (PTX)	SAIP@NPs (Silica/AuNPs with iRGD)	Breast cancer	Integrin αvβ3 targeting; enhanced penetration	Improved tumor retention and efficacy; minimal toxicity.	[72, 73]
Chemotherapeutic co-delivery	Pemetrexed (PEM)	PEM-AuNPs	Lung cancer (A549, H1299)	ROS generation; mitochondrial dysfunction	Enhanced cytotoxicity and apoptosis vs. free PEM.	[212]
AS1411 aptamer targeting	AS1411 aptamer	AS1411-GNPs/Fs-GNPs	Breast cancer	Nucleolin receptor binding	Selective cytotoxicity to cancer cells; minimal normal cell impact.	[213]
Thio-derivative functionalization	Dihydroartemisinin (DG)	AuNPs-MPAm1-DG	PCa	Enhanced cytotoxicity; reduced normal cell damage	Favorable size and drug loading for targeted therapy.	[214]
Vitamin D3 pathway modulation	Vitamin D3 (VD3)	VD3-GNPs	Breast cancer (MCF-7, MDA-MB-231)	Downregulation of ETV7, Hippo, PI3K/AKT/mTOR pathways	Reduced migration/invasion (> 45%); low-dose efficacy.	[79]
Folate receptor-mediated imaging	Folate derivative	Ph-GNP (Phospholipid-AuNPs)	General malignancies (HeLa, LLC)	Folate receptor overexpression	Increased tumor accumulation in folate receptor-positive cells.	[215]
PSMA-targeted imaging	Anti-PSMA antibody	PEG-GNPs	PCa	PSMA-mediated tumor uptake	Validated XFCT/CT imaging for non-invasive monitoring.	[70]

One of the most promising strategies for enhancing the specificity of cancer therapy is the functionalization of AuNPs with tumor-specific ligands. By selectively binding to overexpressed receptors on the surface of cancer cells, these functionalized nanoparticles ensure targeted drug delivery. Folate receptor-targeted AuNPs, for example, have been widely studied due to their overexpression in various cancers. Tamoxifen-loaded β-cyclodextrin nanocomposites (Tam-β-CD-HA-Chi-Au) have demonstrated a 38% reduction in IC50 in Caco-2 colon cancer cells, suggesting their potential in overcoming chemoresistance by targeting folate receptor overexpression [67]. Similarly, AuNPs conjugated with folate and encapsulating doxorubicin (DOX) exhibited 96% drug encapsulation efficiency and significantly enhanced cytotoxicity in prostate cancer (PCa) cells, underscoring the advantages of ligand-mediated specificity in targeted therapy [68].

In addition to folate receptors, the epidermal growth factor receptor (EGFR) has been targeted for its role in tumor progression. Anti-EGFR antibody-conjugated AuNPs improved the therapeutic index by 40% in non-small cell lung cancer (NSCLC) 3D models, emphasizing the importance of EGFR-driven uptake in enhancing treatment efficacy [69] (Fig. 4A). Moreover, prostate-specific membrane antigen (PSMA)-targeted AuNPs have enabled dual-modal XFCT/CT imaging in PCa, providing real-time tracking of tumor accumulation with 95% correlation to ICP-MS validation, which could significantly improve diagnostic precision and therapeutic outcomes [70] (Fig. 4B).

Fig. 4.

Gold nanostructures in precision oncology: cutting-edge pharmacological distribution methodologies. A Diagrammatic illustration of the formulation of DTX-loaded PEGylated AuNPs and subsequent Anti-EGFR conjugation. Reproduced with permission [69]. Copyright from Elsevier Ltd, 2020. B Assessment of the targeting efficacy of PSMA-specific gold nanoparticles (GNPs) in cancer cells. Reproduced with permission [70]. Copyright from Elsevier Ltd, 2021. Utilization of darkfield microscopy equipped with a custom darkfield filter on an Axio Vert.A1 microscope at 200x magnification. Examination of antibody-conjugated GNP internalization in LNCaP (PSMA positive) and PC3 (PSMA negative) cell lines. Fluorescence microscopy images were obtained using a Zeiss Axio Vert.A1 microscope at 200x magnification. Visualization of mouse anti-PSMA antibodies conjugated to GNPs was achieved using Alexa Fluor 488 conjugated anti-mouse secondary antibodies. Scale bar: 50 µm. Quantitative analysis of Alexa Fluor 488 signal foci relative to DAPI nuclei signals. Blocking assays involved pre-treatment with unlabeled PSMA antibodies prior to administration of active-/passive-targeting GNPs. Scale bar: 50 µm. Transmission electron microscopy (TEM) imaging of LNCaP and PC3 cells post-treatment with active-/passive-targeting GNPs (indicated in red). C A detailed schematic representation of the assembly of the DOX-Apts-CS-AuNPs complex, its intravenous administration, the intracellular trafficking of the complex, and the subsequent release of DOX from the complex. Reproduced with permission [71]. Copyright from Elsevier Ltd, 2020. D The graphical abstract of iRGD-Guided silica/gold nanoparticles for efficient tumor-targeting and enhancing antitumor efficacy against breast cancer. Reproduced with permission [73]. Copyright from Dovepress Taylor & Francis Group, 2024. E. Engineering of FUdR-incorporated DNA sequences for the synthesis of af-F/AuNPs and schematic representation of the fabrication process of Dox^@af-F/AuNPs. Reproduced with permission [74]. Copyright from Springer Nature, 2020. F. Assessment of the therapeutic efficacy of AuMSS formulations in HeLa carcinoma cells. Reproduced with permission [77]. Copyright from Elsevier Ltd, 2024. Diagrammatic depiction of cytotoxicity assays involving AuMSS nanomaterials subjected to NIR laser exposure. Evaluation of the cytotoxic effects of AuMSS and AuMSS/PEI/RBC nanorods (100 and 200 µg/mL) both with and without AO encapsulation under NIR irradiation. Positive control (K⁺): cells treated with ethanol; Negative control (K^-): cells without nanoparticle exposure; K NIR: cells without nanoparticle exposure subjected to NIR laser irradiation

Aptamers and peptides are gaining increasing recognition as effective targeting agents due to their high specificity, stability, and ability to penetrate deep into tumor tissues. Tumor-penetrating aptamers, such as AS1411, when conjugated to AuNPs, facilitate the co-delivery of chemotherapeutic agents alongside gene-targeting molecules, thereby enhancing therapeutic efficacy. For instance, AS1411 aptamer-conjugated AuNPs co-delivered DOX and FOXM1 aptamers to breast cancer cells, inducing 70% apoptosis while sparing normal cells, thereby demonstrating the efficacy of synergistic gene-drug interactions [71] (Fig. 4C). Similarly, peptide-guided systems such as the iRGD peptide exemplify spatial precision in drug delivery. Silica/AuNPs loaded with paclitaxel were able to penetrate αvβ3 integrin-rich tumors, achieving 50% longer intratumoral retention and inducing 70% apoptosis by enhancing vascular permeability. This highlights the critical role of spatial precision in increasing the retention and therapeutic efficacy of nanoparticles within tumors [72, 73] (Fig. 4D).

Combating drug resistance remains critical for improving cancer therapy. Researchers are engineering gold nanoparticles (AuNPs) to concurrently deliver multiple drugs, a strategy that amplifies treatment efficacy while hindering resistance development. DNA-hybridized AuNPs co-loaded with fluorodeoxyuridine (FUdR) and doxorubicin (DOX) exemplify this approach, achieving 90% apoptosis in HER2-positive breast cancer cells via combined DNA damage and topoisomerase inhibition. This result demonstrates how combinatorial nanotherapeutics can overcome resistance pathways [74] (Fig. 4E). Similarly, β-cyclodextrin-functionalized gold nanorods (AuNRs) co-encapsulating melphalan and curcumin utilized NIR-II irradiation to trigger pH-responsive drug release. This platform significantly lowered systemic toxicity without compromising tumor-killing potency, delivering precisely controlled therapy [75].

Stimuli-responsive AuNPs offer precise drug deployment in response to tumor microenvironment (TME) cues like pH shifts. Acid-sensitive designs exploit the acidic tumor niche to minimize off-target release. For instance, pectin-coated AuNPs loaded with DOX (DOX-PEC-AuNPs) achieved 80% payload release in acidic conditions via ASGPR receptor-mediated uptake in HepG2 liver cancer cells, markedly enhancing tumor specificity and lowering whole-body toxicity [76]. Furthermore, red blood cell membrane-cloaked AuMSS nanorods integrate chemotherapy with photothermal therapy (PTT). This dual-action system eradicated cervical cancer cells by combining drug delivery with localized hyperthermia, proving particularly effective against deep-seated lesions [77] (Fig. 4F).

Theranostic platforms, which integrate therapeutic and diagnostic capabilities, represent an exciting advancement in AuNP-based cancer treatment. PSMA-targeted AuNPs have been utilized for dual-modal XFCT/CT imaging in PCa, enabling real-time monitoring of treatment responses and tumor progression [70]. Similarly, bovine serum albumin-functionalized AuNRs (BSAFA-AuNRs) have been used to deliver RNaseA to colon cancer spheroids, inducing RNA degradation and cell death while facilitating fluorescent tracking of the nanoparticles, making them valuable tools for both therapeutic and diagnostic applications [78]. In addition to their direct therapeutic effects, AuNPs can be utilized for immune modulation to enhance the anti-tumor immune response. Vitamin D3-conjugated AuNPs (VD3-AuNPs) have been shown to downregulate key signaling pathways, such as PI3K/AKT/mTOR and Hippo pathways, resulting in a 45% reduction in metastasis in breast cancer models at nanomolar doses, highlighting their potential for immune modulation [79]. Furthermore, computational screening has led to the development of AuNPs with enhanced binding affinity for immune checkpoint molecules, such as PD-L1. Irinotecan-AuNPs, identified through this approach, exhibited a three-fold increase in PD-L1 binding affinity and demonstrated increased toxicity in A549 lung cancer cells, suggesting that computational design can significantly improve the effectiveness of immune-modulatory therapies [80].

AuNPs in gene/RNA delivery and therapy: mechanisms and applications

AuNPs transcend conventional barriers in nucleic acid delivery through ligand-functionalized targeting that enhance tumor-specific uptake while enabling endosomal escape for intracellular payload release [81, 82]. Innovations in stimuli-responsive architectures exploit TME cues (pH/enzymes) to achieve spatiotemporal control of CRISPR/Cas9 and siRNA cargos, minimizing off-target effects [83].

Despite their advantages, AuNP-based gene delivery faces inherent challenges in nucleic acid stability and endosomal escape efficiency compared to established lipid or polymeric vectors. Unmodified siRNA/CRISPR complexes adsorbed onto AuNPs exhibit significantly reduced serum stability due to nuclease degradation [84, 85]. Covalent conjugation strategies (e.g., disulfide linkages) or nucleic acid backbone modifications can enhance resistance to enzymatic degradation [86, 87]. AuNPs demonstrate lower endosomal escape efficiency than proton-sponge polymers (e.g., PEI) or ionizable lipid-based systems [88]. This is particularly critical for CRISPR-Cas9 ribonucleoproteins (RNPs) [89]. Engineering approaches such as fusogenic peptide conjugation or photothermal-triggered endosome disruption improve cytoplasmic delivery [90, 91]. AuNPs typically possess lower nucleic acid loading capacity than lipid or polymeric nanocarriers [92]. Hybrid architectures overcome this limitation by integrating AuNP targeting capabilities with high-capacity polymeric encapsulation [93–95].

Advanced nanocarriers including AuNP-liposome hybrids and peptide-modified nanorods further optimize RNA stability and metastasis suppression via sustained gene silencing [96, 97]. We additionally examine synergistic RNA-chemotherapy co-delivery platforms and epigenetic modulation strategies that potentiate radiotherapy efficacy. Functionalized AuNPs for advanced nucleic acid delivery in cancer therapy was showed in Table 3.

Table 3.

Functionalized AuNPs for advanced nucleic acid delivery in cancer therapy

Gene/RNA Type	Delivery Carrier	Targeting Strategy	Tumor Type	Key Mechanism	Main Outcomes	References
PLK1 siRNA	PEGylated Au-PEI-PEG-AA nanoparticles	Anisamide receptor targeting	PCa	siRNA escapes endosomes; RelA gene silencing	Significant tumor suppression in xenografts; synergy with paclitaxel.	[107]
STAT3 siRNA	FA-conjugated AuNPs-PEI	Folate receptor-mediated uptake	PCa	Receptor-mediated endocytosis; lysosomal escape	Enhanced gene silencing in LNCaP cells; low toxicity.	[98]
HER2 siRNA	AuNPs coated with 11-MUA, CaCl2, PEI	Multilayer assembly for stability	Breast cancer (MCF-7)	HER2 gene silencing via siRNA delivery	IC50 = 45.35 nM; HER2 expression reduced by 18.94-fold.	[102]
DOX + PLK1 siRNA	PEI-coated AuNPs	pH-sensitive drug release	Breast cancer	Co-delivery of DOX and siRNA; synergistic effect	Enhanced efficacy in 2D/3D tumor models.	[101]
Chemo-drug + siRNA	Au-siRNA@aptamer nanocages	MMP-2 enzyme-triggered release	Lung cancer	Selective tumor delivery; siRNA protection	High gene delivery efficiency; controlled drug release.	[99]
CRISPR/Cas9 (E6 oncogene)	pH-responsive AuNCs	pH-dependent assembly/disassembly	Cervical cancer	Nuclear delivery of SpCas9; E6 knockout	Restored p53 function; apoptosis induction with minimal normal cell toxicity.	[100]
MICU1 siRNA	Auroliposomes (AuNP-loaded liposomes)	Lysosomal avoidance	Ovarian cancer	Altered intracellular uptake pathway	> 85% gene silencing at low siRNA dose; validated in vitro and in vivo.	[103]
siRNA (EMT inhibition)	Multivalent peptide-functionalized AuNRs	Peptide-mediated delivery	Metastatic breast cancer (TNBC)	Inhibition of EMT process	Suppressed metastasis in zebrafish xenograft models.	[104]
miRNA modulation	PEGylated AuNPr	Radiosensitization	Metastatic PCa	Downregulation of miRNA-95, −106, −145, −541−3p	Improved radiotherapy sensitivity; personalized treatment based on miRNA profiles.	[105]
miRNA-33a + AuNPs	Cationic PEGylated liposomes (C-PEG-Nio)	Cationic lipid-enhanced delivery	Breast cancer (MCF-7)	Co-delivery of AuNPs and miRNA-33a	Lowest IC50 (34.49% encapsulation), highest apoptosis rate, upregulated BAX/BCL2 ratio.	[106]

A notable advantage of AuNPs is their ability to be functionalized with specific ligands that enable targeted delivery to cancer cells. Tumor-specific ligands facilitate precise recognition and uptake of therapeutic nucleic acids, thus minimizing off-target effects and improving therapeutic efficacy. Folate receptor-targeted systems have demonstrated considerable success, particularly in PCa therapy. For example, AuNPs functionalized with polyethyleneimine (PEI) and folic acid (FA) exhibited threefold higher gene silencing in LNCaP PCa cells compared to non-targeted delivery systems, primarily through folate receptor-mediated uptake and PEI-enhanced endosomal escape [98]. Similarly, aptamer-guided delivery systems have shown significant promise in achieving dual-targeting capabilities. For instance, Au-siRNAaptamer nanocages selectively delivered siRNA and chemotherapeutics to lung tumors using matrix metalloproteinase-2 (MMP-2)-cleavable peptides, leading to an impressive 80% inhibition of tumor growth [99] (Fig. 5A).

Fig. 5.

Mechanisms and applications of AuNPs in gene/rna delivery and therapeutics. A The schematic depiction of the synthesis of gold nanocages and their tumor-targeted gene and doxorubicin (DOX) release mechanism. Reproduced with permission [99]. Copyright from Springer Nature, 2021. Initially, gold nanoparticles were functionalized with thiolated DNA-2 and thiolated anti-VEGF siRNAs utilizing the thiol-gold affinity. PAA-1 was conjugated with ssDNA-1, ssDNA-3, and the AS1411 aptamer, while PAA-2 was attached to ssDNA-1, ssDNA-4, and the AS1411 aptamer. Subsequently, the ssDNA-2 and siRNA-modified (DNA-2: siRNA = 1:10 molar ratio) gold nanoparticles were combined with equimolar quantities of PAA-1, PAA-2, and DNA-5 to construct the robust framework of the gold nanocages. Ultimately, the assembly of the gold nanocages was completed through complementary base pairing of DNA-3 and DNA-4 with DNA-5. B siRNA-cLPs were internalized into cancer cells through multiple pathways including macropinocytosis, clathrin-, and caveolae-mediated endocytosis. Reproduced with permission [103]. Copyright from American Association for the Advancement of Science(AAAS), 2020. However, the incorporation of a small quantity of 20-nm AuNP into cLPs altered the internalization mechanism of AuroLPs to predominantly caveolae-mediated endocytosis (CvME). The transition from multiple internalization routes to a singular pathway was substantiated through three methods: (i) assessment of uptake in the presence of specific chemical inhibitors, (ii) silencing of pathway-specific target proteins, and (iii) measurement of PP2A enzymatic activity. The CvME route for AuroLPs uptake conferred several benefits, including reduced lysosomal degradation attributed to decreased PP2A activity, enhanced gene silencing efficiency, and improved antitumor efficacy in two ovarian cancer models

To further enhance the precision and control of gene delivery, stimuli-responsive AuNPs have been developed that release their therapeutic payloads in response to specific environmental cues, such as pH or temperature. These systems offer enhanced spatiotemporal control over drug release, enabling targeted therapy at the tumor site while minimizing systemic toxicity. An exemplary application involves pH-responsive AuNCs self-assembled with CRISPR/Cas9, which dissociate in the acidic TME to enable nuclear delivery of Cas9 to cervical cancer cells. This platform effectively silenced the E6 oncogene, reactivated p53 tumor suppressor function, and triggered programmed cell death while exhibiting minimal collateral damage to healthy tissues [100]. Another significant example involves polyethyleneimine-coated AuNPs carrying both PLK1 siRNA and doxorubicin (DOX) via acid-cleavable linkages. In 3D tumor models, this combinational system exerted 2.5 times greater cell-killing activity compared to single-agent treatments, highlighting the advantage of merging gene silencing with chemotherapy [101].

Combining RNA therapeutics with conventional chemotherapeutics using AuNP carriers creates potent synergy to counter drug resistance and amplify anti-tumor effects. This integrated strategy mutually reinforces both therapeutic modalities, yielding superior tumor control. For instance, in HER2-positive breast cancer models, researchers employed HER2-siRNA-conjugated AuNPs co-delivering DOX. This approach suppressed HER2 expression 18.94-fold while reaching potent cytotoxicity (IC₅₀ = 45.35 nM) [102]. Similarly, DNA-hybridized AuNPs co-loaded with fluorodeoxyuridine (FUdR) and DOX proved highly effective, inducing apoptosis in 90% of HER2⁺ cancer cells through simultaneous induction of DNA damage and topoisomerase blockade—further validating co-delivery efficacy [74].

To boost RNA stability and delivery efficiency, researchers are creating advanced nanocarriers. These sophisticated designs shield fragile nucleic acids from degradation, enhance cellular uptake, and overcome biological barriers. Auroliposomes—liposomes embedding gold nanoparticles—exemplify this progress. Engineered to evade lysosomal destruction in ovarian cancer cells, this system achieved > 85% MICU1 gene knockdown at low siRNA doses and significantly inhibited tumor growth in animal models [103] (Fig. 5B). This hybrid approach effectively merges the protective lipid encapsulation with the plasmonic properties of AuNPs for photothermal-triggered endosomal release, addressing two core limitations of standalone AuNPs. Additionally, multivalent peptide-functionalized AuNRs have shown promising results in treating TNBC. These nanoparticles inhibited epithelial-mesenchymal transition (EMT) and reduced metastasis by 70% in zebrafish models through sustained siRNA delivery [104]. These advanced carrier systems represent significant improvements in the protection, stability, and delivery of RNA therapeutics.

AuNPs play a pivotal role in gene editing and miRNA-based therapies, both of which are gaining increasing attention as promising strategies in cancer treatment. CRISPR/Cas9 systems delivered via pH-responsive AuNCs have been successfully employed for precision genome editing in cervical cancer, where restoration of the p53 tumor suppressor gene led to apoptosis induction [100]. In PCa, PEGylated AuNPs have been used to modulate specific miRNAs, such as miRNA-95, −106, and − 145, enhancing radiosensitivity and enabling personalized low-dose radiotherapy [105]. In miRNA co-delivery, cationic PEGylated liposomes loaded with AuNPs and miRNA-33a demonstrated a fourfold upregulation of the pro-apoptotic BAX/BCL2 ratio in MCF-7 breast cancer cells, highlighting the therapeutic potential of miRNA-based treatments in cancer [106].

The development of integrated platforms that combine gene therapy with other therapeutic modalities, such as chemotherapy, is emerging as a promising strategy to combat metastasis and improve clinical outcomes. For example, PLK1 siRNA-loaded Au-PEI-PEG-AA nanoparticles, combined with paclitaxel, effectively suppressed NF-κB signaling in PCa, resulting in synergistic tumor inhibition in xenograft models [107]. This combinatorial approach enhances the effectiveness of treatment by targeting multiple pathways involved in tumor progression and metastasis, offering new therapeutic avenues for the management of advanced-stage cancers.

AuNPs in combination cancer therapy: synergistic strategies and advanced systems

AuNPs serve as versatile platforms for synergistic cancer therapy, integrating photothermal-chemotherapy to overcome drug resistance through localized hyperthermia-enhanced tumor penetration and selective drug release [108–110]. Their capacity to potentiate photodynamic-immunotherapy regimens further remodels immunosuppressive TME via ROS amplification and immune checkpoint modulation [24]. Advanced ligand-directed systems and stimuli-responsive nanoplatforms achieve spatiotemporal precision, while multimodal theranostics unify real-time imaging with therapeutic actions [111]. Collectively, these combinatorial strategies exemplify transformative approaches for precise tumor eradication across diverse cancer types. The synergistic cancer therapy via engineered AuNPs platforms was showed in Table 4.

Table 4.

Engineered gold nanoparticle systems for multimodal cancer therapy: synergistic mechanisms and clinical translation

Combination Therapy	Delivery Carrier	Tumor Type	Key Mechanism	Main Outcomes	References
Chemo + Photothermal	PGNS	HER2+ Breast cancer	Apoptosis induction via microtubule/caspase-3/HSP70 pathways; M2 macrophage inhibition	Tumor suppression via CT/PA/PT imaging and chemo-photothermal synergy.	[112]
PTT + Gene Therapy	DNAi-conjugated AuNPs (42 nm)	Breast cancer (MCF-7)	Size-dependent cellular uptake; photothermal conversion under NIR	Highest cytotoxicity and photothermal efficiency in 42 nm AuNPs.	[114]
PDT Targeting Cancer Stem Cells	AuNP-Antibody Conjugates (NBC)	Lung cancer stem cells (CSCs)	Targeted delivery of photosensitizer (AlPcS4Cl) to CSCs	Enhanced PDT efficacy; significant CSC cytotoxicity.	[117]
PTT + PD-L1 siRNA	Polymer-coated Au Nanorods (GNPs-siRNA)	Lung cancer	PD-L1 gene silencing + PTT/PA imaging	Synergistic inhibition of tumor growth in vitro and in vivo.	[123]
PDT + Gene Silencing	Flower-like AuNPs (GNFs-siRNA)	Pan-cancer	BAG3 gene silencing to inhibit heat shock response	Improved tumor suppression under laser irradiation.	[216]
PDT with Enzyme-Triggered Release	GC-coated SiNC-AuNC Nanocages	Glioblastoma	pH/enzyme-triggered release of photosensitizer	Stronger phototoxicity and tumor suppression with cleavable peptide linkers.	[125]
PTT/PDT/Chemo + TRPV6 Inhibition	PTX-PP@Au NPs	Androgen-resistant PCa	Heat/ROS generation under NIR; TRPV6 channel blockade	Synergistic tumor suppression; reduced systemic toxicity.	[217]
PTT	Au-Cur Nanostructures	Breast cancer (4T1)	808 nm laser-enhanced photothermal conversion	Higher cytotoxicity under 808 nm vs. 650 nm laser.	[218]
EGFR-Targeted PDT	Peptide-conjugated PEG-AuNPs	EGFR+ cancers (A549)	Selective targeting via EGFR peptide; C11Pc photosensitizer delivery	Nanomolar-level phototoxicity with minimal dark toxicity.	[121]
pH-Responsive PTT	GSH-coated AuNPs (3 nm)	Pan-cancer	pH-selective targeting of TME; renal clearance	Selective cancer cell toxicity; reduced liver/spleen accumulation.	[124]
Chemo/Radiotherapy + PTT	Alginate hydrogel (Cisplatin + AuNPs)	Pan-cancer	Triple-mode therapy (chemo/RT/PTT)	Complete tumor regression in mice; localized synergistic effects.	[219]
Chemo-Photothermal	AuNP-5-FU Conjugates	Colorectal peritoneal metastasis	Selective tumor accumulation; immune activation	Controlled spatiotemporal drug/heat delivery; reduced off-target toxicity.	[113]
Dual pH/NIR-Responsive PTT + Chemo	Liposome@GNS (PTL-Lips@CS@GNS)	Pan-cancer	pH-triggered drug release + NIR-induced hyperthermia	Synergistic antitumor effects combining traditional medicine and nanotechnology.	[220]
Ocular PTT	Bipyramidal AuNPs (BipyAu@Citrate)	Ocular tumors	Surface chemistry-dependent photothermal conversion	40 °C temperature rise under NIR; controlled collagen distortion without cytotoxicity.	[221]
PTT/PDT + Hypoxia Modulation	CeO2@AuNRs (PA/Ce6)	Liver cancer	CeO2 alleviates hypoxia; AuNRs generate heat/ROS under NIR	Tumor growth inhibition in vitro/vivo; no acute toxicity.	[116]
PTT/PDT	IR780-loaded AuMSS Nanorods	Cervical cancer (HeLa)	Dual-functionalized AuMSS with PEG-CH3/gelatin; enhanced cellular uptake	Effective HeLa cell ablation under combined therapy.	[222, 223]
Radiosensitization	Smart GNRs with PEG/peptide coating	General cancer	Cathepsin B-triggered GNR exposure in TME	Delayed tumor growth and improved survival post-radiotherapy.	[224]
NIR-Triggered PTT/PDT/Chemo	Dumbbell TiO2/AuNRs@mS-MTX: UCNP	Deep-seated tumors	UCNP-enabled NIR activation of TiO2 (PDT)/AuNRs (PTT)/MTX (chemo)	Enhanced antitumor efficacy in vitro and in vivo.	[225]
Embolization + Chemo/Photothermal	AuNR@NCMC/DOX nanocomposites	Breast cancer	NIR-triggered aggregation for vascular embolization + DOX release	Enhanced tumor targeting; stronger growth inhibition vs. non-NIR treatment.	[226]
Stepwise PTT + Chemo	BP/AuNRs/thermosensitive liposomes scaffold	Pan-cancer	BP degradation controls temperature for Dox release	Early-stage PTT-chemo synergy; post-release MSC proliferation for tissue regeneration.	[227]
PDT + PTT	AuNR/TiO2 hybrids	General cancer	NIR-induced •OH generation via electron transfer from AuNR to TiO2	PDT efficacy > PTT alone; stabilized by hydrophilic ligands.	[115]
Dual-Targeted PDT/PTT	HA-g-(mPEG/Teta-LA/TCPP/FA)-AuNRs	Breast cancer (MCF-7)	HA/FA dual targeting; enhanced ROS and lysosomal escape	Superior cytotoxicity vs. monotherapy in vitro.	[228]
NIR-II PTT + Chemo	USGRV-17-AAG vesicles	Solid tumors	UCST polymer-based thermoresponsive 17-AAG release + 65.1% photothermal efficiency	98.86% tumor growth inhibition in mice.	[229]
Thermodynamic/PTT	ASAPP (AuNRs + AIPH)	Hypoxic tumors	NIR-II-triggered heat and oxygen-independent alkyl radicals	Enhanced tumor ablation in vitro/vivo.	[230]
PTT + Chemo (GSH-responsive)	oMSN-GNR (mesoporous silica-coated GNR)	Liver cancer	GSH-sensitive DOX release + PTT	Synergistic tumor suppression in mice.	[231]
PTT/Chemo/Immunotherapy	ECNVs (AuNR/Gemcitabine/CpG/PD-L1 aptamer)	Pan-cancer	M1 macrophage-derived targeting + PA imaging-guided drug release	Complete tumor regression via ICD and T-cell activation.	[118]
NIR-II PTT + Immunotherapy	GNR-SNO@MMT (tLyP-1-MM-coated AuNR)	Breast cancer (4T1)	NO-mediated vascular normalization + TIME remodeling	94.7% tumor inhibition; 2.4×CD8+ T-cell infiltration.	[119]
PTT/PDT/Chemo	BP/AuNRs/CDs/Dox nanocomposite	Pan-cancer	BP-enhanced PTT/PDT; CDs for imaging/ROS catalysis	Synergistic tumor ablation in vitro/vivo.	[232]
Photoimmunotherapy	CEG (CeO2-deposited AuNRs)	TNBC	NIR-induced ROS/heat for ICD + PD-1 blockade	Enhanced CTL infiltration; reversed immunosuppression.	[120]
PTT/Chemo/Immunomodulation	EcN-Dox-Au microrobots	Pan-cancer	pH-sensitive Dox/AuNR delivery to hypoxic regions	Complete tumor regression without recurrence.	[233]
Mild PTT + Immunotherapy	AuNR@SiO2 (20 nm shell)	Pan-cancer	Sustained mild heating (44–45 °C) for ICD + anti-PD-L1	Primary tumor eradication; prevented recurrence.	[234]
Targeted Chemo/Phototherapy	Dox-Fe@FA-AuNPs	HeLa, MDA-MB-231	pH-dependent Dox release + ROS generation under red light	Selective cytotoxicity in folate receptor + cells; inhibited migration.	[235]
Sequential Chemo/PTT	AuNP-decorated liposomes	Pancreatic cancer	Phase transition-triggered FOLFIRINOX release + PTT	Superior efficacy vs. monotherapy in pancreatic cancer models.	[236]
Targeted PDT	ZnPcS4-AuNP-Anti-GCC conjugates	Colorectal cancer (Caco-2)	Anti-GCC antibody targeting + 3D MCTS model validation	Improved PDT efficacy in 3D tumor spheroids.	[237]
Radiotherapy + PTT	Au@Alg-DA NPs	Breast cancer	X-ray-enhanced ROS + NIR-triggered hyperthermia	Effective cancer cell destruction; no cytotoxicity.	[126]
Immunotherapy (MDSC targeting)	Au-H6 NPs	PD-1-resistant tumors	NLRP3 inflammasome disruption in MDSCs + reduced IL-1β	Enhanced T-cell activation; improved anti-PD-1 response.	[238]
PDT/PTT	g-C3N4/SnS2@Au heterostructure	Liver cancer	Type I/II PDT pathways + 41% photothermal efficiency	80% apoptosis in vitro; enhanced in vivo efficacy.	[239]
PTT + Immunotherapy	T-cell membrane-coated sAuPNCs (bmNP)	Pan-cancer	NIR-II PTT-induced ICD+T-cell membrane-mediated immune modulation	Reduced tumor immune evasion; prevention of recurrence via immune memory.	[240]
Radiotherapy + Immunotherapy	M-Au@RGD-NM (STING agonist-coated AuNPs)	Radioresistant tumors	ROS/DNA damage-enhanced RT + STING pathway activation	Increased CD8+ T-cell infiltration and M1 macrophage polarization.	[241]
Targeted PDT	FA-Au/PAA Janus NPs (5-ALA loaded)	Breast cancer (MCF-7)	FA-mediated targeting + 5-ALA-triggered ROS generation	High cytotoxicity under laser irradiation.	[122]
Theragnostic (Imaging + Chemo)	FAQDs/AuNRs multilayer nanocapsules	Colorectal (HCT-116), Laryngeal (HEp-2)	pH/ultrasound-triggered 5-FU release + enhanced ultrasound/fluorescence imaging	High anticancer activity in vitro; real-time tumor tracking.	[127]
CT Imaging + Chemo	Pemetrexed/PEG-PNIPAM-coated AuNPs	Breast cancer (4T1, MDA-MB-231)	FA receptor targeting + thermo-responsive drug release	2–4× higher X-ray attenuation vs. Visipaque; tumor-specific accumulation.	[242]
Photoimmunotherapy	AuHQ (CTSE-triggered AuNP/AIE assembly)	Pancreatic cancer	CTSE-mediated AuNP aggregation + ICD induction	Fluorescence-PA imaging-guided therapy; enhanced antitumor immunity with IDO1 inhibitor.	[24]
Self-Activated PTT/PA Imaging	H2O2-responsive mAuNP/Lu NPs	Pan-cancer	CL-triggered AuNP aggregation + enhanced tumor retention	Overcame limited light penetration depth; activated PA imaging and PTT.	[128]

The combination of PTT and chemotherapy has emerged as a potent strategy for enhancing cancer treatment outcomes. AuNPs, particularly porous gold nanoshells (PGNS), serve as dual-functional platforms capable of both heat generation upon NIR irradiation and controlled drug delivery. For instance, Herceptin^®-functionalized PGNS, loaded with DM1, resulted in 90% tumor suppression in HER2⁺ breast cancer by combining redox-responsive drug release with localized hyperthermia [112] (Fig. 6A). In colorectal cancer, AuNPs co-delivered 5-FU, selectively accumulating in peritoneal metastatic tumor nodules, leading to a remarkable 98% inhibition of tumor growth through chemo-photothermal synergy [113]. Additionally, size-optimized AuNPs, conjugated with Bcl-2 DNAi, demonstrated enhanced cellular uptake and photothermal cytotoxicity in MCF-7 cells, with a temperature increase of 15 °C under NIR irradiation [114] (Fig. 6B). These findings underscore the potential of combining PTT with chemotherapy to enhance the therapeutic index and overcome treatment resistance.

Fig. 6.

Integration of AuNPs in oncological treatments: synergistic methodologies and cutting-edge systems. A Illustration of the preparation of DM1-mPEG/HER-PGNSs and its antitumour mechanism. Reproduced with permission [112]. Copyright from Springer Nature, 2021. B Schematic of DNAi-conjugated Au-NPs endocytosis into MCF-7 cells. Reproduced with permission [114]. Copyright from Dovepress Taylor & Francis Group, 2020. C Principle of the synthesis of hybrid AuNR/TiO2 nanoparticles and of their in photodynamic therapy. Reproduced with permission [115]. Copyright from American Chemical Society, 2023. D Schematic illustration for photoacoustic imaging-guided phototriggered precision chemoimmunotherapy. Reproduced with permission [118].Copyright from American Chemical Society, 2022. E Illustration of biomimetic gold nano-modulator for deeptumor NIR-II photothermal immunotherapy via gaseous microenvironment remodeling strategy. Reproduced with permission [119]. Copyright from Springer Nature, 2025. F Schematic illustration of the combination therapy of photoimmunotherapy synergizes with PD-1 blockade in triple-negative breast cancer using CEG NRs. Reproduced with permission [120]. Copyright from Multidisciplinary Digital Publishing Institute(MDPI), 2023. G Schematic illustration of the synthetic procedure of GNPs-hPD-L1 siRNA and their applications in vivo. Reproduced with permission [123].Copyright from Elsevier Ltd, 2019. H Scheme of pancreatic cancer-specific AuNP-based phototheranostic modulator (AuHQ). Reproduced with permission [24]. Copyright from American Chemical Society, 2024

The integration of PTT with PDT provides a powerful strategy to maximize tumor destruction. AuNPs, particularly AuNRs, have been extensively utilized to amplify ROS generation, which plays a crucial role in PDT’s effectiveness. For example, AuNR/TiO2 hybrid systems produced cytotoxic hydroxyl radicals under NIR irradiation, leading to 80% apoptosis in cervical cancer cells through dual PTT/PDT [115] (Fig. 6C). In hepatocellular carcinoma, CeO2-modified AuNRs alleviated tumor hypoxia and enhanced ROS production, resulting in 95% tumor growth suppression [116]. Furthermore, antibody-conjugated AuNPs loaded with AlPcS4Cl significantly increased PDT efficacy threefold compared to free photosensitizers in lung cancer stem cells [117]. This combination of PTT and PDT enhances the tumor-killing effect through synergistic ROS generation and alleviation of hypoxia, providing a promising treatment avenue for various cancer types.

AuNPs are also leveraged to modulate the TME, potentiating immune responses and thereby improving the efficacy of immunotherapies. For example, M1 macrophage-derived nanovesicles, co-loaded with AuNRs and gemcitabine, induced immunogenic cell death (ICD), resulting in a 2.4-fold increase in CD8⁺ T cell infiltration into tumors [118] (Fig. 6D). Similarly, biomimetic AuNR regulators, such as GNR-SNO^@MMT, combined NIR-II PTT with nitric oxide (NO)-mediated reprogramming of the TME, achieving 94.7% tumor suppression in breast cancer [119] (Fig. 6E). In TNBC, CeO2-AuNRs activated the STING pathway, enhancing the efficacy of PD-1 blockade therapy [120] (Fig. 6F). These studies emphasize the potential of AuNPs to enhance anti-tumor immune responses by remodeling the TME and synergizing with immunotherapeutic strategies.

Precision medicine is a cornerstone of modern cancer therapy, and AuNPs offer an innovative platform for ligand-mediated targeted delivery of therapeutic agents. For instance, EGFR-targeted AuNPs functionalized with FITC-βAAEYLRK-C11Pc selectively induced PDT in A549 lung cancer cells at nanomolar concentrations [121]. In breast cancer, folate-decorated Janus nanoparticles (NPs) effectively delivered 5-aminolevulinic acid (5-ALA) to MCF-7 cells, resulting in 90% cytotoxicity under laser irradiation [122]. Additionally, for PCa, PD-L1 siRNA-conjugated AuNPs not only silenced immune checkpoints but also generated hyperthermia, leading to a 70% reduction in tumor volume [123] (Fig. 6G). These targeted delivery systems allow for precise therapy with minimal off-target effects, highlighting the potential of AuNPs in personalized cancer treatments.

The development of environmentally triggered nanoplatforms has significantly advanced the precision and control of cancer therapies. AuNPs can be engineered to respond to various external stimuli, such as pH, temperature, and enzymatic activity, to release their therapeutic payloads selectively at tumor sites. For example, pH-sensitive GSH-AuNPs accumulate in the acidic TME, enabling selective PTT with renal clearance and minimizing systemic toxicity [124]. Enzyme-cleavable AuNCs, such as GC-pep^@SiNC-AuNC, were utilized to release IR780 in glioblastoma, achieving 50% longer intratumoral retention, thereby enhancing therapeutic effects [125]. Additionally, ultrasound-responsive alginate-AuNPs enhanced ROS generation under X-ray exposure, synergizing with radiotherapy and PTT to improve treatment efficacy [126]. These stimuli-responsive systems provide precise temporal and spatial control, optimizing the therapeutic index and minimizing side effects.

AuNPs also play a pivotal role in multimodal theranostics, combining diagnostic imaging and therapeutic functions into a single platform. FA-quantum dot/AuNR nanocapsules, for instance, enabled fluorescence and ultrasound-guided 5-FU release, resulting in 85% tumor suppression in HCT-116 xenografts [127]. In another study, H2O2-activated CL-AuNPs aggregated in the TME, enhancing photoacoustic contrast and PTT efficacy, thereby improving both imaging and therapeutic outcomes [128]. Moreover, for pancreatic cancer, CTSE-responsive AuHQs self-assembled into imaging-detectable clusters, achieving complete tumor remission in combination with IDO1 inhibitors [24] (Fig. 6H). These multimodal theranostic systems not only allow for real-time monitoring of therapy but also enhance the precision and effectiveness of cancer treatments.

AuNPs in cancer diagnosis, imaging, and theranostics

AuNPs revolutionize cancer diagnostics through multimodal imaging platforms, where SERS achieves single-molecule sensitivity and Gd-doped systems enhance MRI/CT contrast for precise tumor localization [129, 130]. Ligand-directed probes further enable molecular subtype discrimination and microlesion detection via photoacoustic imaging at < 0.5 mm resolution. Stimuli-responsive theranostics exploit TME cues for synchronized imaging and controlled drug release, while SERS-guided intraoperative tools delineate tumor margins with 100 μm spatial precision. These innovations establish closed-loop diagnostic-therapeutic cycles from early detection to surgical intervention. AuNPs-based precision oncology platforms: from molecular diagnosis to guided therapy was showed in Table 5.

Table 5.

AuNPs-based precision oncology platforms: from molecular diagnosis to guided therapy

Application Type	Delivery Carrier/System	Tumor Type	Key Mechanism	Main Outcomes	References
Theranostic (PDT)	EGF/Ce6-functionalized AuNPs (BN)	TNBC	EGFR targeting; ROS-mediated apoptosis/necrosis	86% TNBC cell death; 9× higher ROS vs. normal cells.	[134]
Imaging + Therapy	Curcumin-conjugated Au clusters (CUR-AuNCs)	Cervical cancer	Red fluorescence imaging; selective cytotoxicity	High stability; low toxicity to normal cells.	[243]
Stable Imaging	PEG-SH/MPA dual-ligand AuNPs	Pan-cancer	PEG-SH stabilization; anti-EGFR antibody conjugation	Enhanced colloidal stability; targeted cancer cell imaging.	[149]
Glioblastoma Theranostics	GC-coated SiNC-AuNC nanocages	Glioblastoma	Enzyme-cleavable peptide linker; pH-responsive release	Stronger phototoxicity vs. free photosensitizer.	[125]
Multimodal Therapy	PTX-PP@Au NPs (gold-caged nanoparticles)	Androgen-resistant PCa	PTT/PDT/CT synergy; TRPV6 channel inhibition	Reduced systemic toxicity; tumor suppression.	[217]
Targeted Drug Delivery + Imaging	CUR/AuNP-loaded HNTs (CS-coated)	Pan-cancer	pH-responsive CUR release; NIR imaging	Enhanced anticancer activity in acidic TME.	[244]
PDT Nanoconjugates	Phthalocyanine-based nanoconjugates	Pan-cancer	Tumor-selective ROS generation; improved solubility/penetration	Reduced off-target toxicity; enhanced PDT efficacy.	[245]
SERS Sensing	Anisotropic silica-coated AuNRs	Pan-cancer	Tip-specific silica coating; electrostatic analyte adsorption	Enhanced SERS sensitivity for cationic dyes (e.g., methylene blue).	[246]
Multimodal Imaging + Immunotherapy	GSMM (GNR/SiO2/MnO2@MDSC membrane)	Pan-cancer	Mn2+-activated STING pathway; ICD	Enhanced antitumor immunity; MRI/PAI/PTI capabilities.	[247]
Lung Cancer Theranostics	Au@MnO2@PM (homologous cell membrane)	Lung cancer	NIR-II PTT; CT/MRI/PTI multimodal imaging	Tumor growth inhibition; no systemic toxicity.	[137]
SERS + PTT	SiO2@Au NSs (gold nanostars)	Breast cancer	High SERS enhancement (1.37 × 106); photothermal conversion (72% efficiency)	Effective in vitro photothermal ablation.	[131]
Chemotherapy Monitoring	P2AuNPs (DOX-conjugated polymer/AuNPs)	Pan-cancer	pH/GSH-responsive DOX release; fluorescence recovery	Selective cytotoxicity; real-time drug release tracking.	[47]
Electrochemical Biosensor	PEI-AuNP/PMA-modified electrode	Lung cancer	Signal amplification via redox platform	Detection limit: 0.51 pg/mL; validated in urine/serum samples.	[138]
Radiolabeled Imaging	99mTc-labeled folate-AuNPs	Folate receptor + cancers	HYNIC chelation; folate receptor targeting	Tumor uptake observed; specificity unclear.	[248]
Vascular Imaging	sAu/GSH-LF (ultrasmall AuNPs + lactoferrin)	Pan-cancer	Prolonged blood retention (1–3 h); renal clearance	High-resolution micro-CT imaging of tumor vasculature.	[249]
Cancer Cell Detection	MCF sensor (AuNPs/GO/CuO-NFs)	HepG2, MCF-7, A549, etc.	LSPR-based sensing; GLUT receptor targeting (2-DG coating)	High sensitivity/selectivity for multiple cancer cell lines.	[139]
Cancer Subtype Discrimination	Au@PBA NPs (ratiometric Raman probes)	Breast cancer subtypes	EpCAM/EGFR biomarker ratio detection	Quantitative distinction between MCF-7 and MDA-MB-231 cells.	[132]
PCa Biosensor	Con A/GNP-modified capacitive sensor	PCa	PSMA detection via lectin binding; Al-IDE electrode	Linear range: 10 pM–100 nM; LOD: 10 pM.	[135]
pH-Responsive PET Imaging	DOX-AuNPs with citraconic anhydride linkers	Pan-cancer	Acid-triggered DOX release; AuNP aggregation enhances PET signal	High uptake in HeLa cells; clear PET tumor imaging in xenograft models.	[250]
CT/MR Dual-Mode Imaging	Au NP-embedded CSTDs (core-shell dendrimers)	Breast cancer	RGD peptide targeting αvβ3 integrin; Gd chelation for MR contrast	High X-ray attenuation and r1 relaxivity; safe metabolic clearance.	[140]
PAI for Bladder Cancer	GNRs@Chit-Iso4 (α5β1 integrin-targeted)	Bladder carcinoma	Ultrasound-assisted bladder distribution; PAI detects < 0.5 mm lesions	Superior sensitivity over ultrasound/bioluminescence; urine-stable targeting.	[136]
AD Diagnosis via CT Imaging	GNR-D1/Ang2 (BBB-penetrating peptides)	Alzheimer’s disease	Dual peptide targeting amyloid plaques; CT contrast enhancement	Age-dependent CT signal differences in AD mouse models; validated pharmacokinetics.	[141]
SERS-MRI Dual-Modal PD-L1 Detection	GR/IO NPs with anti-PD-L1 antibodies	TNBC	SERS for single-cell sensitivity; MRI for deep tissue monitoring	Accurate PD-L1 expression profiling; potential for immunotherapy guidance.	[251]
Integrated Fiber-Optic Theranostics	iFOT probe (graphene/Au nanostar hybrids)	Deep-seated tumors	Hypoxia-responsive fluorescence; NIR-triggered PTT via single fiber	Combines real-time hypoxia sensing and tumor ablation; compatible with endoscopy.	[252]
Single-Vesicle Cancer Screening	DISVT (plasmonic AuNP-labeled EVs)	Breast cancer	Dual fluorescence/scattering imaging of EV surface proteins	Detects early-stage HER2 ± breast cancer; 3× higher tumor EVs in advanced cases.	[253]
PA Imaging of MMP-9	AuNSs with MMP-9 aptamer/DNA strands	Breast cancer	MMP-9-induced AuNS aggregation; LSPR shift detection via US/sPA	Selective detection in solution, cells, and xenografts; links to metastasis.	[254]
CTC Electrochemical Sensor	MnO2 NSs/AuNPs@DNA aptamers	CTCs	CTC capture via aptamers; MnO2-mediated signal reduction	LOD: 3 cells/mL; validated in clinical samples for rare cell analysis.	[255]
MR/CT-Guided PTT	Gd: AuNPs@SF (silk fibroin-stabilized)	Pan-cancer	Gd doping for MR/CT contrast; SF biocompatibility	Tumor ablation with imaging guidance; no systemic toxicity.	[133]
Intraoperative SERS/PTT	Urchin-like AuNPs	Colon/ovarian cancer	SERS for tumor margin delineation; NIR-triggered aPTT	Prevents recurrence in orthotopic models; supports clinical translation.	[142]
HER2-Targeted PAI	TRA-Aurelia 1/2 NPs	HER2+ breast cancer	Multispectral PAI for HER2+ tumor margins	Reduces false-negative margins in breast-conserving surgery; dual-targeted imaging.	[143]

One of the major advantages of AuNPs is their ability to facilitate high-resolution imaging across multiple modalities, improving both diagnostic accuracy and therapeutic precision. SERS platforms exemplify the potential of AuNPs for ultrasensitive molecular imaging. For instance, SiO₂^@Au nanoshells have demonstrated a SERS enhancement factor of 1.37 × 10⁶, enabling highly sensitive detection of rhodamine B at the molecular level [131] (Fig. 7A). Additionally, AuNPs functionalized with specific biomarker probes, such as Au^@PBA nanoparticles, have shown the ability to distinguish between different breast cancer subtypes, including MCF-7 and MDA-MB-231, through EpCAM/EGFR biomarker ratios [132] (Fig. 7B). Moreover, Gd-doped AuNPs offer dual-mode imaging capabilities, significantly enhancing both X-ray attenuation and T1-weighted MRI contrast, which aids in the precise guidance of PTT [133] (Fig. 7C). These examples underscore how AuNPs optimize multimodal imaging to provide accurate tumor localization and more effective, personalized treatment strategies.

Fig. 7.

Applications of gold nanoparticles in oncologic diagnostics, imaging modalities, and theranostic interventions. A The fabrication of multifunctional silica core-Au nanostars shell and its utilization in Surface-Enhanced Raman Scattering (SERS) amplification and photothermal eradication of breast cancer cells is presented. Reproduced with permission [131]. Copyright from Wiley, 2023. B Stepwise synthesis of EGFR and EpCAM SERS nanoprobes and their Raman signals and the illustration of ratiometric targeting of two SERS nanoprobes to the cell surface. Reproduced with permission [132]. Copyright from Elsevier Ltd, 2021. C The biomimetic synthesis of Gd: AuNPs^@SF and its application in MR/CT dual-modal imaging-guided PTT for precise therapy of tumor. Reproduced with permission [133]. Copyright from Multidisciplinary Digital Publishing Institute (MDPI), 2022. D Scheme of Raspberry-like gold nano-conjugates of block copolymer prodrug based bicontinuous nanoparticles for cancer theranostics. Reproduced with permission [47]. Copyright from Elsevier Ltd, 2025. E Scheme of etched multicore fiber sensor using copper oxide and gold nanoparticles decorated graphene oxide structure for cancer cells detection. Reproduced with permission [139]. Copyright from Elsevier Ltd, 2020. F Scheme of multifunctional core − shell tecto dendrimers incorporated with gold nanoparticles for targeted dual mode CT/MR imaging of tumors. Reproduced with permission [140]. Copyright from American Chemical Society, 2021

The accuracy of cancer diagnosis can be greatly enhanced by targeting specific molecular markers expressed on tumor cells. Ligand-functionalized AuNPs excel in achieving this level of tumor specificity, ensuring that both imaging and therapeutic agents are delivered precisely to cancer cells. For example, EGFR-targeted AuNPs conjugated with chlorin e6 (Ce6-AuNP-EGF) have shown remarkable efficacy in TNBC, inducing 86% cell death through PDT and generating ninefold higher ROS in cancer cells compared to normal cells [134]. In PCa, folate-conjugated AuNPs have enabled the detection of PSMA at concentrations as low as 10 pM using capacitive biosensors, outperforming conventional PSA assays [135]. Furthermore, α5β1 integrin-targeted AuNRs have demonstrated the ability to detect sub-0.5 mm bladder tumors through photoacoustic imaging (PAI), overcoming the limitations of traditional ultrasound imaging [136]. These examples highlight the promise of ligand-functionalized AuNPs in enhancing the specificity and sensitivity of molecular imaging in oncology.

The integration of stimuli-responsive systems within AuNP-based theranostics allows for the controlled release of therapeutic agents in response to specific triggers within the TME, such as pH, enzymes, and redox conditions. This approach not only enhances therapeutic efficacy but also improves diagnostic accuracy. For instance, pH-sensitive P2AuNPs utilize metal-enhanced fluorescence quenching to monitor the release of DOX in tumors, achieving exceptional sensitivity for circulating tumor cell (CTC) detection at concentrations as low as 3 cells/mL [47] (Fig. 7D). Moreover, enzyme-responsive AuNCs have been utilized to release the NIR dye IR780 in glioblastoma, enhancing PTT efficacy by 50% under NIR irradiation [125]. Additionally, redox-sensitive Au^@MnO₂^@PM nanoprobes, combining MRI-guided hypoxia imaging with PTT, have demonstrated a remarkable 94.7% tumor suppression in lung cancer [137]. These stimuli-responsive nanoplatforms offer precise control over drug release, ensuring targeted therapy at the tumor site and minimizing systemic toxicity.

AuNPs have revolutionized cancer biosensing by significantly enhancing the sensitivity and specificity of biomarker detection. Electrochemical sensors incorporating AuNPs functionalized with PEI-AuNPs have demonstrated an impressive sensitivity of 0.51 pg/mL for the detection of GM2AP in urine and serum, proving to be a valuable tool for the early diagnosis of lung cancer [138]. Furthermore, fiber-optic localized surface plasmon resonance (LSPR) sensors functionalized with AuNPs and CuO nanobuds have successfully detected multiple cancer cell lines, such as HepG2 and MCF-7, with over 95% specificity via GLUT receptor targeting [139] (Fig. 7E). These advanced biosensing platforms provide non-invasive, highly sensitive methods for monitoring tumor biomarkers, enabling early detection of cancer and more precise treatment decisions.

AuNPs have paved the way for the development of integrated theranostic systems that combine both diagnostic and therapeutic functions into a single platform. Multifunctional conjugates, such as Au-PAMAM-RGD, enable dual-mode CT/MR imaging of αvβ3 integrin-positive tumors, while simultaneously providing rapid renal clearance and minimal hepatic accumulation [140] (Fig. 7F). Au^@PBA nanoshells have also been utilized to integrate PTT, PDT, and chemotherapy into one platform, achieving 80% apoptosis in cervical cancer cells via caspase-3 activation [115]. Moreover, peptide-coated AuNRs have been employed for Alzheimer’s disease diagnosis, crossing the blood-brain barrier and providing threefold higher CT signals in amyloid-rich regions, thus demonstrating the versatility of AuNPs beyond cancer [141]. These multifunctional theranostic platforms offer a comprehensive approach to cancer treatment by enabling real-time imaging and simultaneous therapeutic intervention.

AuNPs are also transforming surgical practices by providing real-time guidance during tumor resection. Intraoperative tools based on AuNPs allow for more accurate and efficient surgeries. For example, SERS-active AuNPs have been used to delineate tumor margins in colon and ovarian cancer models with spatial resolution as fine as 100 μm, enabling effective residual tumor ablation through postoperative PTT [142]. Additionally, HER2-targeted TRA-Aurelia probes have facilitated real-time multispectral photoacoustic imaging (PAI) during breast-conserving surgery, resulting in a 20% reduction in re-excision rates [143]. These innovative tools enable surgeons to perform more precise tumor removal, minimizing damage to surrounding healthy tissues and improving patient outcomes.

AuNPs in nanocarrier design and stability mechanisms

The biological fate and therapeutic efficacy of AuNPs are governed by intricate nano-bio interactions, where cellular uptake pathways and dynamic protein corona formation critically determine tumor targeting precision [144–147]. Size- and shape-dependent properties—particularly rod-shaped AuNPs for enhanced photothermal conversion versus star-shaped variants for context-specific bioactivity-further dictate therapeutic outcomes. Surface engineering innovations, including PEGylation, aptamer functionalization, and pH-triggered charge-reversal systems, collectively optimize colloidal stability and TME responsiveness. Significantly, engineered AuNPs actively remodel immunosuppressive TME niches through redox modulation and macrophage repolarization, synergizing with PTT for metastatic suppression. The balancing cellular processing, systemic safety, and therapeutic efficacy of clinically-driven design of AuNPs was showed in Table 6.

Table 6.

Clinically-driven design of AuNPs: balancing cellular processing, systemic safety, and therapeutic efficacy

Design/Mechanism	Key Findings	Implications/Applications	References
Nanoparticle-cell interactions (protein corona, endocytosis pathways)	NPs form protein coronas in biofluids; TME and endocytosis mechanisms (e.g., phagocytosis, macropinocytosis) dictate fate.	Guides design of efficient and safe nanomedicine by understanding nano-bio interactions.	[150]
Antibody-conjugated AuNPs (AuNPs-PAA-Ctxb)	Rapid blood clearance; long-term accumulation in liver/spleen; transient liver injury; renal cysts observed post-6 months.	Highlights need for long-term toxicity studies of antibody-functionalized AuNPs.	[164]
Shape-dependent effects of PEGylated AuNPs (spheres, stars, rods)	Rod-shaped AuNPs (AuNPr-PEG) most significantly alter metabolic activity; shape-dependent proliferation effects in PCa cells.	Critical to select optimal AuNP shape/size for cancer therapy.	[160]
Cellular uptake of bare AuNRs in breast cancer cells	SKBR-3 and MCF-7 cells internalize AuNRs via macropinocytosis; NPs aggregate at cell membranes.	Provides insights for designing AuNR-based drug delivery systems.	[148]
Cell membrane- vs. EV-coated AuNRs	Cell membrane-coated AuNRs interact more effectively with tumor cells; CD47 presence reduces macrophage uptake.	Membrane composition (e.g., CD47) is critical for targeted delivery.	[165]
Size-dependent photothermal efficiency of GNRs	Shorter GNRs (aspect ratio 3.3–3.5) require lower laser energy (28 pJ) and induce higher local temperatures.	Optimal GNR size enhances PTT efficacy via compact clustering and electromagnetic coupling.	[159]
Thermal sensitivity of GNR-mediated PTT	6 µg/mL GNR + 4.5 W/cm² laser reduces viability by 94% (4T1) and 87% (Pan02); heat generation correlates with efficacy.	Establishes methodology for evaluating thermal sensitivity in nanoparticle-assisted PTT.	[168]
Lyophilization stability of AS1411-aptamer-functionalized AuNPs	10% sucrose minimizes aggregation; lyophilized AuNPs retain targeting and cytotoxicity in MCF-7 cells.	Enables long-term storage of functionalized AuNPs for cancer targeting.	[162]
AuNPs as electron acceptors disrupting redox balance	Electron transfer from cancer cells to AuNPs induces oxidative stress and apoptosis; efficacy increases with hypoxia.	Novel strategy for targeting cancer redox pathways, especially in hypoxic tumors.	[30]
AgNPs/AuNPs reprogram TAMs	Both NPs shift TAMs to anti-tumor M1-like phenotype; suppress migration and MMP activity.	Potential for modulating TAMs to inhibit tumor progression.	[167]
NanoEL AuNPs enhance tumor vascular leakiness	NanoEL particles disrupt endothelial junctions, increasing drug/nanoparticle penetration; reduces primary/metastatic tumors.	Enhances drug delivery to tumors; applicable to micro-metastases.	[166]
Morphology-optimized NIR-II AuNPs (rods vs. dumbbells)	PEGylated NIR-II AuNPs show superior PA imaging depth, photothermal efficiency, and biocompatibility vs. NIR-I.	Optimizing AuNP shape/aspect ratio improves theranostic performance in deep tissues.	[34]
Size-dependent SERS activity of spherical AuNPs	SERS signal peaks at 60–80 nm; biphenyl-4-thiol labels on 80 nm AuNPs yield strongest signal.	Guides selection of optimal AuNP size and Raman tags for biosensing.	[161]
Charge-reversal AuNPs for metastatic tumor detection	Sub-5 nm AuNPs with tailored HD (2.4–4.2 nm) and zeta potential (−31.2 to −11.4 mV) detect 1 mm metastases.	Enables precise identification of small metastases in liver/lungs for early intervention.	[163]

The interaction of AuNPs with biological systems involves complex cellular uptake mechanisms. Clathrin-mediated endocytosis and macropinocytosis are the principal pathways by which AuNPs are internalized into cells. For example, studies have demonstrated that bare AuNRs exhibit preferential uptake by SKBR-3 and MCF-7 breast cancer cells, with rod-shaped AuNPs being internalized more efficiently than spherical counterparts [148]. Once AuNPs enter the bloodstream, they interact with various proteins in the plasma, forming a “protein corona.” This protein layer plays a significant role in determining the biodistribution, targeting efficiency, and immune system interactions of the nanoparticles. For instance, the addition of polyethylene glycol (PEG) to the surface of AuNPs minimizes nonspecific protein adsorption, enhancing colloidal stability and extending circulation time in vivo [149]. Moreover, the acidic and enzyme-rich nature of the TME can significantly alter the protein corona’s structure and composition, thereby influencing therapeutic outcomes and tissue targeting [150].

Strategies to mitigate protein corona effects

The spontaneous formation of a protein corona presents a major translational hurdle for AuNPs, as it often masks targeting ligands, alters biodistribution, and reduces cellular uptake efficiency. To overcome these challenges, several advanced engineering strategies have been developed. The spontaneous formation of a protein corona poses a significant translational challenge for AuNPs. To address this, advanced engineering strategies have been developed. Polyethylene glycol (PEGylation) remains widely adopted for reducing non-specific protein adsorption through steric hindrance effects [151]. Recent innovations utilize zwitterionic polymers such as poly(carboxybetaine), which leverage superior hydration capacity to minimize protein adhesion while preserving ligand accessibility [152]. An alternative approach involves pre-coating AuNPs with functional proteins like albumin or transferrin, creating engineered “corona shields” that exploit natural transport pathways [153]; albumin-functionalized systems specifically enhance tumor targeting via SPARC receptor-mediated uptake in pancreatic malignancies [154]. For dynamic environmental adaptation, pH-responsive charge-reversal surfaces maintain neutral charge in physiological conditions but undergo protonation-triggered charge switching in acidic tumor microenvironments, shedding adsorbed proteins and revealing concealed targeting motifs [155–157]. Complementarily, nanoscale topographic control through geometrically constrained designs—exemplified by star-shaped AuNPs with sharp vertices—physically restricts large protein adsorption through spatial exclusion effects [158]. Collectively, these synergistic approaches enhance targeting fidelity and therapeutic payload delivery, directly addressing critical bottlenecks in clinical translation. Strategies to overcome protein corona challenges in AuNP-based therapeutics were showed in Table 7.

Table 7.

Strategies to overcome protein Corona challenges in AuNP-based therapeutics

Strategy	Mechanism of Action	Key Advantages	Limitations
Surface PEGylation	Forms a hydrophilic, sterically repulsive layer that reduces protein adsorption via entropy-driven excluded volume effects.	• Prolongs circulation half-life	• Risk of PEG immunogenicity (anti-PEG antibodies)
		• Minimizes macrophage uptake	• Shielding of targeting ligands
		• Established manufacturing protocols	• ABC effect (Accelerated Blood Clearance upon repeated dosing)
Biomimetic Coating	Encapsulates AuNPs with natural cell membranes (e.g., erythrocyte, leukocyte, or cancer cell membranes) to confer “self” recognition.	• Innate immune evasion	• Complex membrane extraction/functionalization
		• Retention of source cell homing capabilities	• Batch-to-batch variability
		• Reduced inflammatory responses	• Scalability challenges
Targeting Ligand Engineering	Conjugates high-affinity ligands (e.g., antibodies, peptides) to AuNP surfaces to competitively bind receptors before corona formation.	• Enhanced active targeting	• Ligand burial by corona proteins during circulation
		• Partial circumvention of corona shielding	• Critical dependence on ligand density/orientation
		• Facilitates theranostic integration	• High production costs
Stimuli-Responsive Deshielding	Incorporates cleavable linkers (e.g., pH/enzyme/ROS-sensitive) to remove protective coatings selectively in target microenvironments.	• Stealth transport + on-demand activation	• Trigger efficiency compromised by TME heterogeneity
		• Spatiotemporally controlled ligand/drug exposure	• Kinetic mismatch between de-shielding and therapy
		• Reduced off-target effects	• Potential carrier destabilization
Zwitterionic Surface Modification	Creates charge-balanced hydrophilic interfaces (e.g., carboxybetaine) that resist protein adhesion through electrostatically induced hydration layers.	• Ultralow nonspecific protein adsorption	• Synthetic complexity of zwitterionic polymers
		• Negligible immunogenicity	• Limited long-term in vivo stability data
		• Broad-spectrum antifouling properties	• Potential interference with biofunctionality
Engineered Pre-Corona Formation	Pre-adsorbs selected functional proteins (e.g., human serum albumin, transferrin) to form a “designer corona” resisting opsonization.	• Customizable bio-interface for specific cell recognition	• Vulnerability to competitive displacement by endogenous proteins
		• Exploits natural protein stealth properties	• Lack of standardized protocols
		• Improved batch reproducibility	• Conformational instability of pre-adsorbed proteins

The size and shape of AuNPs are crucial factors influencing their cellular behavior and therapeutic efficacy. The morphology of AuNPs affects both their cellular uptake and their ability to interact with light for therapeutic applications, such as PTT. Rod-shaped AuNPs, with aspect ratios between 3.3 and 3.5, have demonstrated superior cellular uptake and enhanced photothermal conversion capabilities compared to spherical or star-shaped AuNPs. In PCa models, these rod-shaped particles require only 28 pJ of laser energy to induce apoptosis, highlighting their potential for PTT [159]. In contrast, star-shaped AuNPs have been shown to stimulate the proliferation of LNCaP cells at low concentrations, emphasizing the context-dependent nature of nanoparticle behavior [160]. Furthermore, size optimization plays a critical role in enhancing the performance of AuNPs for imaging applications. For example, spherical AuNPs with diameters between 60 and 80 nm are ideal for maximizing SERS signals, with 80 nm particles yielding the highest SERS activity [161]. These findings underscore the importance of selecting the appropriate size and shape to optimize both therapeutic efficacy and imaging capabilities of AuNPs.

Surface modifications are integral to stabilizing AuNPs and enhancing their functionality for targeted therapy. The development of dual-ligand systems, such as PEG-MPA, has proven effective in stabilizing AuNPs in high-salt environments while facilitating the conjugation of targeting molecules like EGFR antibodies, thereby enhancing tumor targeting and imaging [149]. Additionally, AS1411 aptamer-functionalized AuNPs have demonstrated the ability to maintain colloidal stability after lyophilization with sucrose, preserving their targeting efficacy and cytotoxic effects against MCF-7 breast cancer cells [162]. Another promising approach involves the use of charge-reversal AuNPs with pH-sensitive surface modifications. These nanoparticles, with sizes ranging from 2.4 to 4.2 nm and ζ-potentials between − 31.2 and − 11.4 mV, exhibit selective binding to metastatic lesions in the liver and lungs. Upon exposure to the acidic pH of the TME, these particles undergo charge reversal, promoting site-specific drug delivery [163] (Fig. 8A). Such surface engineering strategies not only enhance the stability and circulation time of AuNPs but also improve their targeting efficiency, making them promising candidates for therapeutic applications.

Fig. 8.

AuNPs in the development of nanocarrier systems and elucidation of stabilization mechanisms. A Scheme of precisely regulated luminescent gold nanoparticles for identification of cancer metastases. Reproduced with permission [163]. Copyright from American Chemical Society, 2020. B Schematic of internalization pathway and differences in the eAuNR and mAuNR interaction for cancer treatment. Reproduced with permission [165]. Copyright from Elsevier Ltd, 2022. C Schematic of gold and silver nanoparticles efficiently modulate the crosstalk between macrophages and cancer cells. Reproduced with permission [167]. Copyright from Dovepress Taylor & Francis Group, 2025

The in vivo behavior of AuNPs, including their biodistribution and potential toxicity, is influenced by their size, surface charge, and conjugation with targeting molecules. For instance, antibody-conjugated AuNPs exhibit rapid blood clearance and preferential accumulation in the liver and spleen, leading to transient hepatic injury. Long-term accumulation in the kidneys can, however, result in renal cyst formation, raising concerns about the long-term toxicity of certain formulations [164]. Membrane-coated AuNRs, on the other hand, exploit CD47 “don’t eat me” signals to evade macrophage-mediated phagocytosis, thereby improving tumor delivery [165] (Fig. 8B). Furthermore, the modulation of size-dependent vascular leakage using NanoEL AuNPs has been shown to enhance intratumoral penetration without promoting metastasis, emphasizing the importance of optimizing particle size to balance therapeutic delivery with minimal off-target effects [166]. These studies underscore the critical need to consider both the biodistribution and toxicity profiles of AuNP-based nanocarriers when designing formulations for clinical applications.

The TME plays a pivotal role in determining the therapeutic efficacy of AuNPs. Recent studies have shown that AuNPs can actively modulate the TME to enhance the therapeutic response. For example, electron-hijacking AuNPs can disrupt the redox balance within hypoxic tumors through bacterial cytochrome-mediated electron transfer, thereby inducing oxidative apoptosis in tumor cells [30]. Additionally, the combination of gold and silver nanoparticles has been shown to repolarize tumor-associated macrophages (TAMs) to an antitumor M1 phenotype, suppressing matrix metalloproteinase activity and reducing metastasis [167] (Fig. 8C). In the context of PTT, NIR-II-optimized AuNPs with aspect ratios greater than 3.5 significantly improve photothermal efficacy and deep-tissue photoacoustic imaging, resulting in 94% cell death in 4T1 breast cancer cells [168]. These findings highlight the potential of AuNPs not only as carriers for targeted therapy but also as agents capable of modulating the TME, enhancing therapeutic outcomes, and inhibiting tumor progression.

The efficacy of AuNP-mediated PTT and PDT is critically governed by nanoparticle morphology, size, and precise tuning of localized surface plasmon resonance (LSPR) to match near-infrared (NIR) therapeutic windows (NIR-I: 700–950 nm; NIR-II: 1000–1350 nm) [29, 33, 169–171]. The LSPR peak position fundamentally determines light-to-heat conversion efficiency in PTT and plasmon-enhanced singlet oxygen generation in PDT [172]. Among various configurations, rod-shaped AuNPs exhibit exceptional plasmonic tunability, where increasing the aspect ratio shifts the longitudinal LSPR peak from visible to NIR-II regions [173, 174]. This enhances absorption cross-sections and tissue penetration capabilities at longer wavelengths, significantly improving phototherapeutic performance. In contrast, spherical AuNPs primarily absorb in the visible range with limited NIR-I tunability, though larger spheres demonstrate increased scattering useful for imaging applications [175]. Core-shell architectures consisting of dielectric cores with thin gold coatings offer broad NIR spectral tunability through core-to-shell ratio optimization, enabling tailored absorption-scattering balance for PTT or imaging. Star-shaped variants generate intense localized electromagnetic fields at their vertices, creating plasmonic “hot spots” that dramatically amplify reactive oxygen species generation when combined with photosensitizers. Beyond intrinsic plasmonics, surface engineering further refines therapeutic outcomes: ligand functionalization enhances colloidal stability and cellular uptake, while hybrid composites leverage plasmonic enhancement to boost catalytic components for amplified PDT efficacy [176, 177]. Consequently, synergistic optimization of AuNP geometry and surface characteristics maximizes light energy utilization and tissue penetration depth, ultimately advancing precision phototherapeutic applications.

AuNPs in clinical trials of cancers

As previously highlighted, AuNPs exhibit potentially beneficial properties in various preclinical studies. However, there are still limited examples of AuNP-based therapies undergoing clinical trials, and to date, no AuNP-based formulations have been successfully incorporated into standard clinical practice. Table 8 presents an overview of clinical trials involving AuNPs for the treatment and diagnosis of diseases.

Table 8.

Clinical trials of gold nanoparticles for cancer treatment and diagnosis

Item Designation	Component/Material	Objective of the Study	Application	Phase/Status	Clinical trials.gov Identifier
Aurimune(CYT-6091)	PEGylated colloidal gold nanoparticles conjugated with recombinant human tumor necrosis factor-alpha	To evaluate the adverse effects and optimal dosage of CYT-6091 in the treatment of patients with advanced solid malignancies	Management of advanced malignant neoplasms	Phase 1 (completed)	NCT00356980
		To investigate the role of TNF in patients undergoing surgical intervention for primary or metastatic malignancies.	Management of primary or secondary neoplasms	Early phase 1 (completed)	NCT00436410
AuroShell	Polyethylene glycol-functionalized silica-gold core-shell nanostructure	To investigate the detrimental impacts of AuroShell in the treatment of patients with refractory or recurrent head and neck malignancies	AuroLase treatment for intractable or relapsed head and neck carcinoma	Pilot study (completed)	NCT00848042
		To assess the therapeutic effectiveness of AuroLase treatment in patients with primary or metastatic pulmonary neoplasms	AuroLase Therapy for Primary or Metastatic Pulmonary Neoplasms	Pilot study (terminated)	NCT01679470
Nanosensors	Auric nanoclusters and carbon allotrope nanotubes	To validate the diagnosis of gastric cancer (GC) via exhaled breath analysis and explore the correlations between breathomics, metabolomics, and transcriptomics	Identifying GC	Observational (completed)	NCT01420588
NU-0129	A Gold Nanoparticle Spherical Nucleic Acid Conjugate	To assess the safety profile of intravenous NU-0129 administration in individuals with recurrent glioblastoma multiforme (GBM) or gliosarcoma (GS)	Treatment of recurrent GBM or GS	Early phase 1 (completed)	NCT03020017

One of the most prominent examples of AuNPs in clinical cancer treatment is Aurimune (CYT-6091), a 27-nm PEGylated gold nanoparticle loaded with recombinant human tumor necrosis factor alpha (rhTNFα). TNFα is a potent anticancer agent, but its clinical use has been constrained by severe side effects. By conjugating rhTNFα to the AuNPs, the drug can be targeted more precisely to tumor sites, reducing its systemic toxicity. Additionally, the PEGylation of the AuNPs helps to prolong their circulation time in the bloodstream and increases their accumulation at the tumor site. The Phase I clinical trial (NCT00356980) of CYT-6091 demonstrated that the drug was safe at doses ranging from 50 to 600 µg/m², with no severe side effects observed, except for mild fevers in the first two patients. Although the trial was primarily focused on safety, some patients experienced partial responses, while others had stable disease, prompting the initiation of a Phase II clinical study to further explore its efficacy [178, 179].

Another example is Auroshell, a silica-gold core-shell nanoparticle with a diameter of 144–150 nm, developed by Nanospectra Sciences Inc. for photothermal cancer therapy. Auroshell accumulates in tumor tissues through the enhanced permeability and retention (EPR) effect and is activated by an external NIR laser, enabling precise tumor ablation with minimal effect on surrounding healthy tissues. Preclinical studies have demonstrated the biosafety of Auroshell, showing that it is well tolerated with no significant toxicity observed after intravenous administration [180, 181]. A clinical trial involving 22 PCa patients demonstrated that Auroshell was well tolerated, with only mild adverse effects, including itching and epigastric discomfort [182]. Building on these results, a subsequent study assessed the combination of Auroshell-mediated laser ablation with MR/ultrasound fusion imaging in 16 PCa patients. After 3 and 12 months, 62.5% and 87.5% of the patients, respectively, showed complete tumor ablation, demonstrating that Auroshell-directed PTT is a promising and safe method for targeted PCa treatment [183].

In addition to these, several other AuNP-based treatments are undergoing clinical trials. Khoobchandani et al. have investigated the use of Nano Swarna Bhasma, an AuNP-based Ayurvedic formulation, for treating metastatic breast cancer. This therapy, which combines AuNPs with mangiferin, has successfully transitioned from preclinical to clinical studies [184]. Moreover, a pilot clinical trial (NCT01420588) developed a gold nanoparticle-based nanosensor for the detection of gastric cancer through breath analysis, marking a significant step toward non-invasive cancer diagnosis. The promising results of this pilot study have laid the foundation for larger, multicenter clinical trials [185].

AuNPs are also showing potential outside of oncology. For example, Pang et al. developed a hydrogel eye patch containing AuNRs coated with palladium, which demonstrated the ability to spontaneously heat up under visible light, thereby relieving dry eyes and moisturizing the eyelid skin. This approach was tested in both animal and human studies, showing excellent safety and efficacy [186]. Additionally, a clinical study (NCT01270139) evaluated two gold nanoparticle-based delivery methods for treating coronary atherosclerosis. One method involved PTT using silica-AuNPs, while the other used a magnetic navigation system to deliver silica-gold iron-bearing nanoparticles. Both methods showed a favorable safety profile, suggesting their potential for clinical application in cardiovascular treatments [187].

Challenges in clinical translation of AuNP-based therapeutics

The clinical translation of AuNPs-based oncology therapeutics faces five interconnected barriers despite promising preclinical outcomes: Manufacturing scalability and standardization hurdles impede clinical-grade production due to inconsistent eco-friendly synthesis and the absence of regulatory guidance for hybrid nanomaterial characterization; Unresolved long-term biosafety concerns persist regarding reticuloendothelial system organ accumulation and potential chronic toxicity manifestations; Dynamic protein corona complexities unpredictably compromise targeting efficiency through opsonization-mediated clearance and ligand masking; Tumor microenvironment delivery barriers, including dense stromal matrices and elevated interstitial pressure, severely restrict intratumoral penetration efficiency; and Regulatory-commercialization ambiguities arising from multifunctionality classification ambiguities, prohibitive production costs, and fragmented intellectual property landscapes. These interdependent challenges necessitate coordinated solutions across material science, regulatory science, and clinical development paradigms.

Discussion and prospects

AuNPs have significantly advanced oncological research, offering revolutionary solutions to longstanding challenges in cancer detection, diagnosis, and therapy. Their remarkable plasmonic properties, coupled with high biocompatibility and multifunctional capabilities, enable AuNPs to overcome barriers traditionally associated with cancer treatment. These nanoparticles exhibit unique optical properties that make them suitable for a variety of diagnostic and therapeutic applications, including imaging, drug delivery, and hyperthermia [34, 113, 188, 189]. The ability to modify their surface chemistry, size, and shape further enhances their versatility, allowing them to be tailored for specific therapeutic and diagnostic needs.

A pivotal advancement in AuNP-enabled theranostics lies in the rational design of stimuli-responsive systems that harness pathological signatures within the TME for spatially and temporally controlled therapeutic intervention. As synthesized in Table 9 and Fig. 9, these sophisticated platforms employ programmable molecular switches-capable of undergoing dynamic physicochemical transformations in response to TME-specific aberrations-to transduce local pathological cues into targeted therapeutic outputs. Key switch mechanisms include environmentally triggered bond cleavage, reversible molecular reconfiguration, and stimulus-induced phase transitions, all engineered to maximize tumor-selective activation. While such systems demonstrate considerable promise, their clinical translation necessitates addressing fundamental challenges in trigger discrimination. Future iterations must refine stimulus recognition fidelity to substantially mitigate off-target effects, particularly for oxidation-responsive architectures where background oxidative tone in healthy tissues may provoke premature payload release. This demands innovations in both switch chemistry and systems-level delivery strategies. Concurrently, advancing in vivo profiling of TME heterogeneity will be critical to inform the precision engineering of next-generation responsive nanoplatforms, ultimately bridging nanomaterial intelligence with biological complexity for clinically viable theranostics.A major area of progress is the development of sustainable, biogenic synthesis methods that employ plant, fungal, and microbial systems. These green synthesis approaches not only provide an environmentally friendly alternative to traditional chemical methods but also introduce bioactive functionalities to AuNPs. The natural synthesis routes contribute to the biocompatibility of the particles, reducing toxicity concerns and enhancing their overall therapeutic potential [190, 191] Importantly, this biogenic approach minimizes the environmental impact associated with the synthesis of AuNPs, a critical consideration in the context of large-scale manufacturing and clinical application. Precision targeting has been another significant advancement, with strategies utilizing ligands, aptamers, and peptides to enhance the specificity of AuNPs for tumor cells while minimizing off-target effects [192–194]. These targeted delivery systems enable AuNPs to selectively bind to cancer cells, improving the therapeutic index of drugs and reducing systemic side effects. The development of integrated theranostic platforms, which combine real-time multimodal imaging with stimuli-responsive drug release, is another breakthrough. These platforms offer spatial and temporal control over drug delivery, enabling highly targeted therapy that can be monitored in real-time, improving both the efficiency and safety of treatments. Moreover, the combination of AuNPs with various therapeutic modalities has demonstrated promising results in overcoming drug resistance and addressing metastatic cancer [113, 195, 196]. Synergistic regimens, such as PTT combined with immunotherapy or gene-chemotherapy combinations, have shown enhanced therapeutic efficacy in preclinical models [197–199]. AuNP-mediated remodeling of the immunosuppressive TME further potentiates the immune system’s ability to target and clear tumor cells. By modulating key components of the TME, AuNPs can help overcome the immune evasion strategies employed by tumors, making them a valuable tool in immuno-oncology.

Table 9.

Stimuli-Responsive mechanisms of gold nanoparticles (AuNPs)

Stimulus Type	Category	Specific Factors	Primary Response Mechanisms	Advantages	Disadvantages
Internal Stimuli	Tumor Microenvironment	Low pH (6.5–7.0)	Cleavage of pH-sensitive bonds (hydrazone, imine); Phase transition of polymers (e.g., polyhistidine)	High biological specificity; Autonomously activated in target tissues	Limited tunability; Variable response across heterogeneous tumors
		High GSH (2–10 mM)	Reduction of disulfide bonds; Thiol-exchange reactions	Exploits intrinsic redox gradient; Biocompatible cleavage mechanism	Off-target release in liver/kidney (high basal GSH); Limited to reducing environments
		Overexpressed Enzymes	Enzymatic cleavage of peptide linkers; De-shielding of surface ligands	High substrate specificity; Amplified signal in disease sites	Enzyme heterogeneity in tumors; Potential inhibition by endogenous inhibitors
		(e.g., MMPs, Cathepsins)
		Elevated ROS/RNS	Oxidation-sensitive bond cleavage (boronate ester, thioketal); ROS-triggered degradation	Active in inflammatory/ischemic regions; Synergy with oxidative stress therapies	Variable ROS levels in vivo; Off-target activation in normal tissues with transient ROS
		(e.g., H2O2, •OH)
		Local Hyperthermia	Phase transition of thermoresponsive polymers (e.g., PNIPAM, LCST ~ 32 °C)	Non-invasive intrinsic trigger	Insufficient temperature gradient for reliable activation; Poor spatiotemporal control
		(Mild, < 2 °C rise)
External Stimuli	Physical Fields	Light (NIR/Vis/UV)	Photothermal effect (PTT); Photochemical reaction (PDT); Photoisomerization; Photocleavage	NIR: Deep tissue penetration, precise spatiotemporal control; Multi-modal applications (PTT/PDT)	Limited penetration depth (< 10 cm for NIR-II); Potential phototoxicity (UV/Vis); Heat dissipation in tissues
		Magnetic Fields	Magnetothermal effect (with composites); Magnetic targeting	Deep tissue penetration; Non-invasive activation; Combinatorial therapy (chemo/hyperthermia)	Requires composite fabrication (Au/Fe3O4); Limited heating efficiency (dependent on field frequency/strength)
		(Static/Alternating)
		Ultrasound (HIFU)	Sonothermal effect; Cavitation-induced mechanical disruption; Sonodynamic therapy (SDT)	Deep penetration (≥ 10 cm); Focal precision; No ionizing radiation	Requires specialized equipment; Inhomogeneous energy distribution; Potential tissue cavitation damage
		X-ray/Ionizing Radiation	Radiation sensitization (dose enhancement); Radiocatalysis; Radiation-induced bond cleavage	Unlimited penetration depth; Synergy with clinical radiotherapy; Activatable in deep-seated tumors	Systemic toxicity risks; Complex radiation shielding requirements; Low energy conversion efficiency
		Exogenous Heating	Thermally induced phase transition (e.g., PNIPAM); Liposome fusion	Uniform heating; Simple implementation	Poor spatial specificity; Non-target tissue exposure; Limited to superficial regions
		(e.g., water bath, RF)

Fig. 9.

Schematic illustration of stimuli-responsive mechanisms in gold nanoparticles (AuNPs).Internal stimuli (e.g., tumor microenvironment-specific low pH, high GSH concentration, specific enzymes, reactive oxygen species (ROS), and localized hyperthermia) can trigger bond cleavage, conformational changes, or phase transitions. External stimuli (e.g., near-infrared light, magnetic fields, ultrasound, X-rays, and exogenous heating) primarily drive AuNP aggregation/disaggregation, drug release, or signal transduction through photothermal/magnetothermal/sonothermal effects, mechanical forces, radiation sensitization, or photochemical reactions, enabling precision theranostic applications. Created by Biorender.com

Despite substantial progress, critical barriers continue to obstruct the clinical adoption of AuNP-based therapies. Reproducibility issues in biologically-mediated synthesis methods hamper large-scale manufacturing scalability. Equally concerning is the limited understanding of AuNP biodistribution over extended periods. While initial pharmacokinetic profiles appear favorable, uncertainties regarding organ-specific accumulation and delayed toxicity warrant resolution before clinical deployment. The spontaneous formation of protein coronae—layers of biomolecules adsorbing onto nanoparticle surfaces in biological fluids—further complicates translation. This phenomenon frequently disrupts targeting precision and diminishes therapeutic efficacy by blocking nanoparticle-tumor cell interactions. Within solid tumors, densely packed stromal matrices often physically impede AuNP penetration, restricting access to malignant cells. The strategic design of AuNP shape and plasmonic tuning offers a promising avenue to overcome this penetration barrier and enhance energy deposition within the tumor core. For gene therapy applications, the limited endosomal escape efficiency and nuclease susceptibility of AuNP-delivered CRISPR/siRNA remain significant translational barriers compared to clinically established lipid vectors. Future designs must prioritize ‘smart’ release mechanisms-such as photoactivatable membrane disruption or TME-responsive polymer shedding-to close the performance gap with alternative platforms while retaining AuNP-specific advantages in targeting and theranostics. Regulatory pathways for multifunctional nanotheranostics also lag behind technological innovation. Standardized characterization protocols for complex AuNP systems remain underdeveloped, creating significant hurdles for clinical translation. Absence of unified guidelines obstructs reliable assessment of formulation safety, efficacy, and batch consistency—directly impacting regulatory approval timelines and commercial viability. However, emerging corona-engineering strategies-including zwitterionic stealth coatings, pre-formed functional coronae, and stimuli-responsive ‘corona shedding’ systems—offer promising solutions to preserve targeting fidelity. The integration of these approaches with computational protein corona prediction tools may further enable precision nanocarrier design tailored to individual patient proteomes.

Addressing these translational roadblocks demands focused research initiatives. Advancing AuNP therapies necessitates implementing rigorous GMP-compliant production standards to guarantee nanomaterial uniformity and quality. Longitudinal investigations in large-animal models must evaluate extended pharmacokinetics, tissue distribution patterns, and chronic immune responses, generating essential safety/efficacy data to support human trials. Enhancing preclinical relevance requires sophisticated tumor models; patient-derived organoids replicating human tumor architecture and microenvironmental complexity offer superior platforms for nanoparticle validation. These systems enable iterative refinement of AuNP designs and delivery strategies to better predict clinical performance.

Next-generation AuNP platforms should incorporate dynamic responsiveness to tumor-specific signals like hypoxia or enzyme activity. Such systems could activate therapeutic payloads exclusively within diseased microenvironments, maximizing precision. Concurrently, developing surface engineering approaches to minimize corona formation will optimize targeting fidelity and cellular uptake efficiency. Multi-ligand surface architectures integrating diverse targeting motifs may further augment tumor selectivity and tissue penetration depth. Foundational mechanistic research should dissect AuNP-cell interactions at single-cell resolution, map intracellular trafficking routes, and assess biosafety implications of surface modifications. Toxicogenomic profiling will illuminate structure-activity relationships, guiding safer nanomaterial design. Personalized approaches show particular promise: AI-driven computational modeling could tailor AuNPs to individual tumor biomarkers and patient-specific TME features. Modular platforms interfacing with liquid biopsy diagnostics would facilitate real-time treatment monitoring, enabling adaptive therapeutic adjustments.

Building upon cutting-edge advancements in nanomedicine, we propose five interconnected design pillars for next-generation AuNPs systems engineered to redefine clinical oncology: the implementation of closed-loop theranostic intelligence integrating biosensing AuNPs with AI-guided feedback for autonomous therapeutic adaptation; the development of dynamically bio-responsive platforms utilizing logic-gated nanomaterials activated only upon concurrent pathological triggers to maximize specificity; the adoption of eco-conscious lifecycle design incorporating biodegradable gold nanostructures with enhanced clearance pathways and sustainable synthesis; the engineering of patient-adaptive modularity through reconfigurable surface interfaces enabling rapid biomarker-targeting personalization; and the strategic deployment of immune-transformative functionalities coordinating checkpoint inhibition with innate immune repolarization. These pillars collectively establish the foundation for precision nanomedicine 2.0—a paradigm shift toward autonomous systems operating at the human-proteome interface to achieve high-specificity tumor eradication with minimal collateral toxicity.

Transformative opportunities exist in synergistic modalities: combining AuNPs with radiotherapy exploits gold’s high atomic number for radiation dose enhancement; epigenetic targeting of cancer stem cells; and autonomous feedback systems triggering biomarker-responsive drug release. These innovations hold potential to redefine oncology standards, enhancing efficacy while reducing toxicity.

Conclusion

This review delineates AuNPs transformative role in cancer theranostics through three pivotal advancements—multifunctional integrationenabling concurrent detection/therapy, translational synergy boosting efficacy/sustainability, and engineered intelligence with context-responsive autonomy—yet persisting barriers (manufacturing inconsistencies, protein corona interference, biosafety concerns) demand urgent resolution via standardized production and renal-clearable designs. Realizing AuNPs’ clinical potential requires multidisciplinary convergence to establish characterization standards and advance toxicity assessment, propelling their evolution from experimental tools toward intelligent theranostic systems capable of real-time tumor sensing with adaptive control, immune-stromal reprogramming, and programmable biodegradation. This paradigm shift, driven by nanotechnology-AI-immunology integration, will transform oncology from reactive treatment to preemptive malignancy eradication.

Abbreviations

TME

Tumor microenvironment

AuNPs

Gold nanoparticles

ECM

Extracellular matrix

PTT

Photothermal therapy

PDT

Photodynamic therapy

5-FU

5-Fluorouracil

5FU-G-AuNPs

5-FU-loaded AuNPs

CR

Catharanthus roseus

ROS

Reactive oxygen species

TNBC

Triple-negative breast cancer

SERS

Surface-enhanced Raman scattering

CAG

Curcumin-graphene-AuNPs

LIPUS

Low-intensity pulsed ultrasound

Tam-β-CD-HA-Chi-Au

Tamoxifen-loaded β-cyclodextrin nanocomposites

DOX

Doxorubicin

PCa

Prostate cancer

EGFR

Epidermal growth factor receptor

NSCLC

Non-small cell lung cancer

PSMA

Prostate-specific membrane antigen

NIR

Near-infrared

AuNRs

Gold nanorods

DOX-PEC-AuNPs

Pectin-AuNPs loaded with DOX

BSAFA-AuNRs

Bovine serum albumin-functionalized AuNRs

VD3-AuNPs

Vitamin D3-conjugated AuNPs

PEI

Polyethyleneimine

FA

Folic acid

MMP-2

Matrix metalloproteinase-2

FUdR

Fluorodeoxyuridine

EMT

Epithelial-mesenchymal transition

PGNS

Porous gold nanoshells

ICD

Immunogenic cell death

5-ALA

5-aminolevulinic acid

NSs

Nanoshells

Ce6-AuNP-EGF

EGFR-targeted AuNPs conjugated with chlorin e6

CTC

Circulating tumor cell

LSPR

Localized surface plasmon resonance

PEG

Polyethylene glycol

TAMs

Tumor-associated macrophages

rhTNFα

Recombinant human tumor necrosis factor alpha

EPR

Enhanced permeability and retention

GMP

Good manufacturing practice

AI

Artificial intelligence

Authors’ contributions

Original draft preparation, allocation, revision, and editing: Lianting Zhuang, Yi Lian, Tiantong Zhu. All authors have read and agreed to the published version of the manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

None.

Consent for publication

None.

Competing interests

The authors declare no competing interests.