Approaches Rooted in DNA Nanotechnology for Diagnosing and Treating Gastric Cancer

Gastric cancer (GC) remains a global health concern, ranking fifth among all malignancies. Its late detection and high mortality rates are attributed to non-specific early symptoms and the inefficiency of current screening methods. Traditional diagnostic tools such as endoscopy and histology are invasive and often miss early-stage tumors. DNA nanotechnology, with its unique properties of biocompatibility and programmability, offers a ray of hope in the fight against GC. This article delves into how DNA nanomaterials are transforming the landscape of GC management, from precise diagnosis to targeted treatment.

Colorimetric DNA biosensor for carcinoembryonic antigen (CEA) detection.. Fig.1 Colorimetric-based DNA biosensor for carcinoembryonic antigen (CEA) detection. (Fonseca W. T., et al., 2025)

DNA Nanotechnology in Gastric Cancer Diagnosis

Biomarkers Detection

CEA (Carcinoembryonic Antigen)

CEA, a well-known tumor marker, is crucial for GC monitoring, despite its low specificity. DNA nanotechnology-based biosensors have significantly enhanced CEA detection. For example, aptamer-functionalized gold nanoparticle (AuNP) systems can change color in the presence of CEA. When CEA binds to the aptamer on the AuNP surface, it causes the AuNPs to aggregate, leading to a color change from red to blue. This visual detection method can achieve a detection limit of 3 ng/mL. Electrochemical sensors, on the other hand, using 3D DNA nanotweezers, can detect CEA at an ultra-low concentration of 4.88 fg/mL. The 3D structure of the nanotweezers provides more binding sites for CEA, enhancing the sensor's sensitivity.

miRNA

Dysregulated miRNAs like miRNA-21 and miRNA-135b are potential biomarkers for GC. Isothermal amplification-based lateral flow biosensors (IA-LFB) combine rolling circle amplification (RCA) with a lateral flow strip for visual detection. In the presence of miRNA-135b or miRNA-21, the RCA reaction is triggered, and the amplified products can be detected on the lateral flow strip, allowing for the differentiation of GC patients from healthy individuals. Fluorescence-based biosensors, such as those using carbon dots (CDs) and T7 exonuclease amplification, can perform ratiometric detection of miRNA-21. The CDs emit fluorescence, and when miRNA-21 hybridizes with the probe, the T7 exonuclease cleaves the probe, changing the fluorescence signal, which can accurately detect miRNA-21 levels.

Circulating Tumor Cells (CTCs) and Exosomes

CTCs, although rare, play a crucial role in GC metastasis. DNA aptamers targeting epithelial cell adhesion molecule (EpCAM), a protein overexpressed on CTCs, can be used for their capture. Dual-aptamer (EpCAM/PTK7)-modified magnetic nanoparticles improve the capture efficiency of CTCs. The number of captured CTCs has been correlated with the chemosensitivity of GC patients, providing valuable information for treatment planning. Exosomes, small vesicles released by cells, carry GC-specific markers. Electrochemical sensors using hemin/G-quadruplex systems can detect exosomes. The hemin/G-quadruplex complex acts as an electrochemical signal generator, and when exosomes bind to the sensor surface, the RCA-amplified signal is enhanced, enabling sensitive exosome detection.

Types of Biosensors

Colorimetric Sensors

Colorimetric sensors based on DNA nanotechnology offer a simple and cost-effective way for GC biomarker detection. AuNPs and DNAzymes are commonly used components. For instance, a test strip assay uses Hg²⁺-assisted AuNP peroxidase-like activity. In the presence of a target biomarker (e.g., CEA), the DNA probe on the AuNP surface changes its conformation, allowing Hg²⁺ to bind and activate the peroxidase-like activity of AuNPs. This leads to the oxidation of a chromogenic substrate, turning the test strip blue. The threshold for biomarker detection can be adjusted by modifying the DNA probe sequence.

Fluorescence Sensors

Fluorescence sensors utilize the fluorescence properties of various nanomaterials combined with DNA-based recognition elements. DNA walkers and hybridization chain reaction (HCR) are often employed for signal amplification. A DNA nanomachine composed of exonuclease III and a DNA walker cascade can detect CEA at 1.2 pg/mL. The exonuclease III cleaves the DNA substrate, releasing the DNA walker, which then moves along the track, triggering a series of fluorescence-generating reactions. HCR, on the other hand, can create a branched DNA structure, greatly amplifying the fluorescence signal in the presence of the target biomarker.

Electrochemical Sensors

Electrochemical sensors provide highly sensitive and label-free detection of GC biomarkers. 3D DNA nanotweezers and catalytic hairpin assembly (CHA) are key techniques. An enzyme-free biosensor using DNA tetrahedrons (TDNs) and CHA can detect CEA at 0.04567 pg/mL. The TDNs provide a stable 3D structure, and the CHA reaction generates an electrochemical signal in the presence of CEA. The signal is proportional to the concentration of CEA, allowing for accurate quantification.

SERS Sensors

Surface-enhanced Raman spectroscopy (SERS) sensors offer ultrasensitive detection of GC-related biomarkers. Combining CRISPR/Cas13a with branched HCR on silver nanorod chips can achieve extremely low detection limits for miRNAs. The CRISPR/Cas13a system specifically cleaves the target miRNA, and the branched HCR amplifies the Raman signal. The silver nanorod chips provide a high-enhancement factor for Raman scattering, enabling the detection of minute amounts of miRNAs.

DNA Nanotechnology in Gastric Cancer Therapy

Chemotherapy with Precision

AS1411-AuNPs
Aptamer-modified AuNPs, such as AS1411-AuNPs, can be loaded with chemotherapeutic drugs like doxorubicin (DOX). AS1411 is an aptamer that specifically targets nucleolin, a protein overexpressed on GC cells. When the AS1411-AuNPs reach the tumor site, they bind to nucleolin on GC cells. Under laser irradiation at a slightly acidic pH (pH 5.0, which is characteristic of the tumor microenvironment), the DOX is released from the AuNPs. This targeted drug delivery system enhances the anti-tumor effect of DOX while reducing its systemic toxicity.

Gene Therapy

Metal-Nucleic Acid Frameworks (MNFs)
Ca²⁺-dependent aptamer-DNAzyme MNFs can be designed to target HER-2-positive GC cells. These MNFs deliver interferon regulatory factor-1 (IRF-1) to the cells. Once inside the cells, IRF-1 can silence the GLUT-1 mRNA, which is involved in glucose metabolism. By disrupting glucose metabolism, the cells' energy supply is cut off, and an increase in reactive oxygen species (ROS) levels occurs, leading to DNA damage and cell death.

Multi-Component DNAzymes (MNAzymes)
HER-2-targeted MNAzymes can specifically cleave GLUT1 mRNA when activated by miRNA-21. In HER-2-overexpressing GC cells, miRNA-21 levels are often elevated. The MNAzymes are designed to recognize both HER-2 and miRNA-21. When activated, they cleave GLUT1 mRNA, inhibiting the pentose phosphate pathway, which is essential for cell survival. This leads to apoptosis in HER-2-overexpressing GC cells.

Phototherapy

Photodynamic Therapy (PDT)
AS1411-aptamer-conjugated chlorin e6 (Ce6) is a promising agent for PDT in GC treatment. Ce6 is a photosensitizer that can generate reactive oxygen species (ROS) under light irradiation. The AS1411 aptamer targets nucleolin-expressing GC cells. Once the AS1411-Ce6 conjugate binds to the tumor cells, laser irradiation at a specific wavelength (e.g., 660 nm) activates Ce6, generating ROS that can kill the tumor cells.

Photothermal Therapy (PTT)
Dual-targeted gold nanoprisms (Au-Apt-TPE@Zn) combine AS1411 aptamers and Zn-tetraphenylethene. The AS1411 aptamer targets nucleolin, and the Zn-tetraphenylethene provides fluorescence and photoacoustic imaging capabilities. Under near-infrared (NIR) laser irradiation, the gold nanoprisms convert the light energy into heat, raising the local temperature and inducing apoptosis in GC cells. The dual-targeting ability ensures that the nanoparticles are specifically delivered to the tumor site, enhancing the therapeutic effect.

Integrated Diagnosis-Treatment Platforms

Split Aptamer Platforms
Split aptamer platforms integrate diagnosis and treatment functions. These platforms consist of fluorophore-quencher-labeled DNA strands that can also load chemotherapeutic drugs. When the split aptamer binds to the target cell (e.g., a GC cell), the conformational change of the DNA strand brings the fluorophore and quencher apart, resulting in fluorescence emission, which can be used for imaging. At the same time, the drug-loaded DNA strand releases the chemotherapeutic drug, providing a combined diagnostic and therapeutic approach.

Microfluidic Chips
Microfluidic chips are another example of integrated platforms. Pump-free microfluidic chips that combine CHA and HCR for SERS-based detection of GC-related circulating tumor DNA (ctDNA), such as PIK3CA E542K and TP53 mutations, can complete the analysis within 13 minutes. These chips can handle small sample volumes, enabling early-stage GC screening with high efficiency.

Challenges and Future Directions

Despite the significant progress in DNA nanotechnology for GC diagnosis and treatment, several challenges remain. The stability of DNA nanomaterials in the bloodstream is a concern, as nucleases can degrade them. Chemical modifications, such as phosphorothioate linkages in DNA, can improve stability. Developing multiplex detection methods that can simultaneously detect multiple biomarkers (CEA, miRNA, ctDNA, etc.) is also crucial for more accurate diagnosis. In terms of clinical translation, the complexity of manufacturing non-nucleic acid components in some DNA-based systems and the differences between pre-clinical models and human patients need to be addressed. Pure nucleic acid-based nanomedicines may offer a more straightforward and cost-effective solution for future clinical applications.

Conclusion

DNA nanotechnology has shown great potential in revolutionizing the diagnosis and treatment of gastric cancer. From ultrasensitive biomarker detection to targeted therapies and integrated diagnosis-treatment platforms, DNA nanomaterials provide unprecedented opportunities. Although challenges exist, continued interdisciplinary research and technological advancements will likely lead to the widespread adoption of DNA-based nanomedicines in GC precision medicine, ultimately improving patient outcomes.

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Reference

Fonseca, Wilson Tiago, et al. "Chemical sensors and biosensors for point-of-care testing of pets: Opportunities for individualized diagnostics of companion animals." ACS sensors 10.5 (2025): 3222-3238.

This article is for research use only. Do not use in any diagnostic or therapeutic application.