The field traces its origins to the 1980s, when Ned Seeman proposed using cross-shaped Holliday junctions as modular building blocks for larger assemblies. By adjusting the sticky ends of these four-arm junctions, researchers could link tiles into increasingly complex two-dimensional patterns, culminating in Winfree’s 1998 demonstration of 2D DNA crystals built from double-crossover tiles. The pivotal breakthrough came in 2006, when Paul Rothemund introduced DNA origami: a long single strand of bacteriophage DNA folded by hundreds of short staple strands into pre-designed shapes of roughly 100 nanometers, from simple triangles to intricate patterns. In 2012, Peng Yin’s group added a third pillar with DNA bricks—short synthetic strands that self-assemble into stable three-dimensional constructs without any long scaffold, each brick functioning as a removable module. Today, complementary strategies such as rolling circle amplification and enzyme-free reactions like hybridization chain reaction and catalytic hairpin assembly allow structural construction and signal amplification to proceed simultaneously under mild, isothermal conditions.

What makes DNA nanostructures so attractive for fighting pathogens is a constellation of biophysical properties. Their geometry can be engineered with near-atomic precision, and that geometry directly governs biological behavior. Tetrahedral DNA nanostructures (TDNs) decorated on nanoparticle cores mimic the spiky architecture of coronaviruses, boosting small interfering RNA delivery efficiency from roughly 20 percent to 95 percent. The structures enter cells through caveolin-dependent and macropinocytosis pathways despite their negative charge, with size, shape, and rigidity each modulating uptake; medium-sized, compact, three-dimensional particles generally perform best. They also penetrate remarkable biological barriers: structures of 75 nanometers or less can reach the dermis, TDNs traverse up to 450 micrometers of skin, and the structures diffuse into bacterial biofilms—the dense, antibiotic-resistant fortresses that thwart conventional therapies.

Equally striking is their antioxidant chemistry. DNA origami scavenges singlet oxygen approximately 50,000 times more efficiently than double-stranded DNA, because folded architectures concentrate guanine active sites at high density. TDNs bind the antioxidant enzyme copper-zinc superoxide dismutase with extraordinary affinity, a dissociation constant of 7.59 × 10⁻¹² molar, and can dampen oxidative stress through the Nrf2/HO-1, MAPK, and NF-κB signaling pathways. Combined with low cytotoxicity below 250 nanomolar concentrations, negligible effects on platelets and red blood cells, high drug-loading capacity through intercalation, groove binding, electrostatic adsorption, or sequence hybridization, and rapid renal clearance of small constructs, these features position DNA nanostructures as unusually benign yet capable nanocarriers.

On the diagnostic front, the review documents detection limits that routinely rival or surpass polymerase chain reaction and ELISA. DNA walkers—dynamic structures that move along programmed tracks—have been coupled with electrochemical readouts to detect Staphylococcus aureus at just 9 colony-forming units per milliliter. A polymethylene blue nanoparticle sensor built on dumbbell hybridization chain reaction pushed S. aureus detection down to a single cell per milliliter in human serum and food samples. Dual-mode photoelectrochemical and surface-enhanced Raman spectroscopy platforms now allow hierarchical screening and confirmation in complex matrices such as fruit juices, while cyclic DNA nanostructure gold nanoparticle tags combined with cascade primer exchange reactions detect E. coli O157:H7 at 1.91 colony-forming units per milliliter with recoveries between roughly 88 and 108 percent in real samples.

Against viruses, tetrahedral frameworks have proven especially powerful. TDN-supported field-effect transistors detect SARS-CoV-2 nucleic acid in about 80 seconds without extraction or amplification, reaching limits of one to two copies per 100 microliters of clinical sample. DNA nanobait structures identify multiple respiratory viruses simultaneously at the single-molecule level without reverse transcription or pre-amplification, and a bipedal DNA walker paired with strand displacement amplification achieves attomolar sensitivity with single-base resolution in 15 minutes. Beyond detection, spatially patterned icosahedral DNA nanocages carrying up to 30 neutralizing aptamers block the SARS-CoV-2 spike–ACE2 interaction across variants including Omicron, and cone-shaped DNA origami traps physically engulf pleomorphic virus particles larger than 100 nanometers, from influenza A to Zika and chikungunya. Star-shaped designer DNA architectures display aptamers in patterns that precisely match dengue virus surface antigens, functioning as both sensor and inhibitor.

Therapeutic applications extend deep into antibacterial medicine. TDNs delivering the antimicrobial peptide GL13K enhanced activity against E. coli and restored efficacy against Porphyromonas gingivalis, and an injectable thermosensitive hydrogel system co-delivering GL13K with C/EBPα small activating RNA is being developed for periodontitis, offering anti-inflammatory and osteogenic benefits alongside antibacterial action. TDN–clindamycin complexes lowered the minimum inhibitory concentration eightfold against methicillin-resistant S. aureus in infected bone defect models. DNA origami platforms carrying lysozyme within five wells and 14 targeting aptamers homed in on Bacillus subtilis and E. coli, while a bactericidal origami co-loading G4/hemin DNAzyme and levofloxacin breached bacterial membranes and accelerated infected wound healing in vivo. Antisense oligonucleotide delivery by TDNs has silenced biofilm-forming genes in Streptococcus mutans, and six-helix bundle structures co-delivering antisense RNA with silver ions showed synergistic killing of both gram-positive and gram-negative bacteria.

The technology is not without serious bottlenecks. DNA nanostructures depend on cations such as magnesium to neutralize electrostatic repulsion, so physiological media can trigger disassembly, and nucleases degrade unprotected structures rapidly. The hundreds of custom oligonucleotides required for origami are expensive, and laboratory fabrication resists scale-up to good manufacturing practice standards. Regulatory pathways remain ambiguous, batch-to-batch consistency is difficult to guarantee, and assembly byproducts arising from kinetic traps and thermodynamic competition depress yields. Pathogen-specific obstacles compound these challenges: biofilm extracellular matrices impede penetration even though TDNs achieve 44-fold stronger fluorescence at 20-micrometer biofilm depth than linear structures; RNA viruses mutate rapidly enough to escape single-target therapeutics, though multivalent, multi-epitope DNA scaffolds offer a hedge; and fungal cell walls of bewildering structural variability limit drug access, even as TDNs improve delivery of the antifungal peptide Histatin 5 against Candida albicans.

The outlook nevertheless points toward integration. The review’s authors propose stability benchmarks—structures retaining more than 80 percent integrity after 24 hours in human serum—alongside xenonucleic acid backbones, disulfide crosslinking, and oligolysine-PEG coatings to harden constructs against serum and nucleases. Double-blind validation across at least 500 clinical samples is framed as the gateway to diagnostic approval, while microfluidic chips, lyophilized paper-based formats, and artificial intelligence-assisted design promise point-of-care deployment by non-specialists. On the preventive side, DNA origami vaccine scaffolds have orchestrated antigen and CpG adjuvant spacing to elicit durable immune responses, DNA–RNA hybrid origami shows ribonuclease resistance suitable for mRNA vaccines, and inhalable DNA nano-adjuvants have activated lung-resident memory immunity against pneumonic plague in mice. Perhaps most compelling is the prospect of convergent platforms: single DNA nanostructures that detect an infection, deliver the therapeutic payload, and prime immunity—all from the same molecule that carries life’s code.

Subject of Research: Applications of DNA nanostructures in the detection, treatment, and prevention of pathogenic microorganisms

Article Title: Advances in DNA nanostructures for pathogenic microorganisms

Article References: Han, X., Zhang, J., Pang, S., Wei, G., Niu, J., Lu, Y., & Xi, J. (2026). Advances in DNA nanostructures for pathogenic microorganisms. Materials Today Bio, 40, Article 103591. https://doi.org/10.1016/j.mtbio.2026.103591

Image Credits: AI Generated

DOI: Not provided

Keywords: DNA nanostructures, DNA origami, tetrahedral DNA nanostructures, pathogen detection, antibacterial therapy, antiviral therapy, biosensors, drug delivery, biofilms, SARS-CoV-2, CRISPR diagnostics, nanomedicine