Gold Nanoparticles: Advancing Diagnostic and Therapeutic Applications in Medicine – A Comprehensive Review

Abstract

Metal-based medicines have a 4,000‑year legacy, with platinum compounds pioneered by cisplatin over four decades ago. Recent advances show that metallic nanoparticles, particularly gold nanoparticles (AuNPs), exhibit unique physicochemical traits that surpass their bulk counterparts. AuNPs are FDA‑approved for roles in drug delivery, photothermal therapy, imaging contrast, radiosensitization, and gene transfection. This review surveys AuNPs’ diagnostic and therapeutic potentials, highlights clinical trial‑approved systems, addresses safety concerns, and outlines future directions for safer, more effective nanomedicines.

Introduction

Nanotechnology has unlocked a new era in diagnostics and therapeutics. AuNPs, prized for their stability, tunable size, and strong thiol affinity, can be functionalized with targeting ligands, imaging agents, or therapeutics. Their large surface area allows simultaneous attachment of multiple moieties, enabling precise delivery, real‑time imaging, and synergistic therapy. AuNPs retain the biocompatibility of bulk gold yet offer enhanced cellular uptake and pharmacokinetics. Their clinical potential spans drug carriers for late‑stage cancers, photothermal agents for prostate cancer and acne, and more.

Gold Nanoparticles

AuNPs are solid colloids ranging from 1–100 nm. Their surface plasmon resonance (SPR), shape, and chemistry dictate optical, catalytic, and biological behavior. Two main synthesis routes exist: top‑down physical methods (e.g., milling, lithography) and bottom‑up chemical approaches. The latter, exemplified by the Turkevich citrate reduction, yields 15–150 nm spheres; alternative reducers (NaBH₄, CTAB, ascorbic acid) enable size and shape control. Emerging greener methods—microwave‑induced plasma‑in‑liquid and plant‑based synthesis—eliminate toxic chemicals and improve biocompatibility.

Synthesis Overview

AuNP synthesis: citrate reduction (A) vs. Brust–Schiffrin two‑phase approach (B). Sources: De Gruyter (2013). TOAB tetrabutylammonium bromide, SH thiolated molecules.

Biological Applications of AuNPs

Gold’s long‑standing medical use (since 2600 BC) and demonstrated non‑toxicity underpin AuNP biocompatibility. AuNPs’ high surface area enables conjugation of targeting ligands, imaging dyes, and drugs. Functionalization occurs primarily via gold‑thiol chemistry, but biotin‑streptavidin and carbodiimide coupling also contribute. AuNPs excel in three domains: drug delivery, diagnostics, and therapy.

Drug Delivery

AuNPs address challenges of conventional drugs: low bioavailability, rapid clearance, and resistance. Their small size (≤ 100 nm) facilitates EPR‑mediated tumor accumulation and cellular uptake. AuNPs protect cargo from proteolysis, extend circulation, and enable targeted release. Applications include cancer (cisplatin, doxorubicin), obesity, and acne. Multifunctional AuNPs co‑deliver drugs and targeting ligands, enhancing efficacy and reducing off‑target toxicity.

Diagnostic Platforms

AuNPs’ optical properties (LSPR, SERS, fluorescence quenching) support diverse biosensors. Lateral flow assays (LFAs) commonly use 30–40 nm AuNPs for colorimetric detection of viral RNA, bacterial antigens, and antibodies. For example, an AuNP‑ASO assay detected SARS‑CoV‑2 RNA within ~10 min, with a limit of detection of 0.18 ng/µL. These assays are instrument‑free, rapid, and cost‑effective.

Colorimetric SARS‑CoV‑2 detection using ASO‑capped AuNPs. Reproduced from ACS Nano (2020).

Imaging Contrast

AuNPs’ high atomic number and electron density provide superior X‑ray attenuation compared to iodine. Targeted AuNPs conjugated to PSMA or nucleolin aptamers achieved >4‑fold CT signal enhancement in prostate or lung cancer models. In vivo CT of collagen‑binding AuNPs revealed persistence in blood up to 6 h, far exceeding iodine half‑life. Similar performance is reported for photoacoustic, nuclear, ultrasound, and MRI contrast.

In vivo CT imaging of collagen‑targeted AuNPs (A) and lymph node targeting (B). Reproduced from Elsevier (2018).

Fluorescence and FRET Applications

Quantum‑sized AuNPs (≤5 nm) exhibit fluorescence and act as efficient FRET quenchers. AuNP‑based electrochemical immunosensors achieved pg/mL sensitivity for PSA and neuron‑specific enolase. FRET systems enable real‑time monitoring of biomarker binding and intracellular gene expression.

Bio‑barcoding Assays

Magnetic‑micro‑particle–AuNP barcoding enables ultrasensitive detection of proteins and nucleic acids, surpassing ELISA by 5 orders of magnitude. Examples include HIV‑1 p24 and PSA detection at fg/mL levels.

AuNP‑Based Therapies

AuNPs can act as therapeutic agents themselves (e.g., antioxidant, anti‑angiogenic, anti‑inflammatory) or as drug carriers. Unmodified AuNPs display anticancer, anti‑arthritic, and anti‑obesity effects via ROS generation and EPR accumulation. Surface functionalization with drugs, peptides, or aptamers further enhances specificity and efficacy.

Photothermal Therapy (PTT)

AuNPs convert NIR light to heat within picoseconds, enabling deep‑tissue hyperthermia. AuNRs, nanocages, and nanospheres are tailored for superficial or deep tumors. PTT synergizes with chemotherapy (e.g., Dox, 5‑FU) and immunotherapy, enhancing tumor cell death while sparing normal tissue.

Antimicrobial and Antiviral Actions

AuNPs disrupt bacterial membranes, generate ROS, and inhibit gene expression, overcoming MDR pathogens. Conjugation with antibiotics (kanamycin, cefaclor) restores potency against resistant strains. AuNPs also exhibit antiviral activity against influenza, measles, dengue, and HIV by delivering antiviral agents or directly neutralizing virions.

Gene Therapy and Transfection

AuNPs serve as non‑viral vectors with high transfection efficiency in vitro and in vivo. Cationic AuNPs loaded with siRNA or plasmids achieve >70% knockdown, outperforming commercial reagents. Their conductive surface also enhances electroporation efficacy.

Toxicity Considerations

While AuNPs are generally inert, size, shape, charge, and surface chemistry influence biodistribution and toxicity. Small particles (<2 nm) penetrate organelles, potentially causing irreversible damage; larger particles (>15 nm) remain cytoplasmic. Neutral, PEGylated surfaces reduce protein corona formation and clearance by the reticuloendothelial system (RES). Dosage, exposure time, and administration route also affect safety. Ongoing studies aim to optimize surface coatings and green synthesis to mitigate risks.

Clinical Applications

Several AuNP formulations have entered clinical trials. CYT‑6091 (27‑nm cAuNPs loaded with TNF‑α) demonstrates tumor‑selective accumulation and improved safety compared to free cytokine. AuroLase® (silica‑gold nanoshells) is approved for photothermal acne treatment. Emerging trials evaluate AuNPs for head/neck cancers, lung tumors, and metabolic disorders. These successes underscore the translational potential of AuNPs while highlighting the need for rigorous safety profiling.

Conclusion and Future Perspectives

Gold nanoparticles offer a versatile platform for simultaneous diagnostics, imaging, and therapy. Continued refinement of synthesis, functionalization, and green chemistry will expand clinical adoption. Addressing toxicity through surface engineering and comprehensive in vivo studies remains essential to fully realize AuNPs’ therapeutic promise.

Availability of Data and Materials

All data referenced herein are sourced from peer‑reviewed publications.

Abbreviations

5‑FU

5‑Fluorouracil

AuNPs

Gold nanoparticles

AuNPsQ

Quantum‑sized AuNPs

AuNRs

Gold nanorods

AuNSs

Gold nanospheres

BCA

Bio‑barcoding assay

cAuNPs

Citrate‑capped AuNPs

COVID‑19

Severe acute respiratory syndrome‑coronavirus‑2

CT

Computed tomography

DSF

Disulfide‑flanked peptide

EPR

Enhanced permeability and retention

FRET

Fluorescence resonance energy transfer

HAuNSs

Hollow AuNSs

PEG

Polyethylene glycol

PT

Photothermal

PTT

Photothermal therapy

RES

Reticuloendothelial system

ROS

Reactive oxygen species

TRMs

Tissue‑resident macrophages