Peptide Nucleic Acid Applications in Molecular Genetics

Peptide nucleic acids (PNAs) are synthetic analogues of DNA in which the sugar–phosphate backbone is replaced by a neutral peptide-like scaffold. This modification endows PNAs with exceptional hybridisation affinity and sequence specificity, resistance to enzymatic degradation and remarkable thermodynamic stability. In molecular genetics, PNAs have been exploited as antisense and antigene agents to modulate transcription and translation, as tools for site-specific genome editing via triplex formation, and as molecular probes in diagnostic and biosensing platforms. Recent advances have extended their utility to reversible supramolecular assemblies, in vivo and in utero gene editing through nanoparticle delivery, and selective antimicrobial strategies. These developments underline the global significance of PNAs across therapeutic interventions, precision diagnostics and fundamental studies of gene regulation.

Research from Nature Portfolio

Recent studies have demonstrated the design of a reversible supramolecular anticoagulant constructed from two PNA-conjugated fragments that assemble noncovalently via complementary hybridisation. The resulting bivalent thrombin inhibitor exhibits picomolar potency in vivo and can be rapidly neutralised through administration of a complementary PNA antidote, offering on-demand control of coagulation.

Innovations in γ-substituted PNAs combined with nanoparticle delivery and stem cell factor stimulation have enabled efficient correction of a β-globin gene mutation in adult murine haematopoietic stem cells. Intravenous administration of nanoparticles carrying γPNAs and donor DNA restored normal haemoglobin levels, reduced reticulocytosis and reversed splenomegaly with minimal off-target effects.

Extending this approach to the prenatal setting, polymeric nanoparticles loaded with PNAs and donor templates have been safely delivered to fetuses, achieving in utero correction of a monogenic blood disorder. Treated animals exhibited sustained postnatal elevation of haemoglobin, improved survival and no detectable mutations at partially homologous loci, indicating a versatile route for early gene therapy.

Peptide Nucleic Acid Applications in Molecular Genetics publication trend

The graph below shows the total number of articles in peptide nucleic acid applications in molecular genetics across all publications each year (not limited to Nature Index journals).

Technical terms

Peptide Nucleic Acid (PNA): A synthetic analogue of DNA or RNA in which the nucleobases are attached to a neutral peptide-like backbone, conferring high binding affinity and stability.

Antisense Oligomer: A short strand of nucleic acid or analogue designed to bind complementary mRNA sequences and inhibit translation.

Triplex Formation: The binding of a third strand of nucleic acid or analogue to the major groove of duplex DNA via Hoogsteen or reverse-Hoogsteen hydrogen bonds, used to direct site-specific genome editing.

Nanoparticle Delivery: The use of nanoscale carriers to transport therapeutic agents, such as PNAs and donor DNA, across biological barriers into target cells or tissues.

Supramolecular Assembly: A reversible, noncovalent aggregation of molecular components—here, PNA-conjugated fragments—that can be disassembled by a complementary strand or antidote.

Siderophore: A small, high-affinity iron-chelating molecule produced by microorganisms; synthetic mimics can be conjugated to PNAs to facilitate bacterial uptake.

References

1. Development of supramolecular anticoagulants with on-demand reversibility. Nature Biotechnology (2024).
2. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nature Communications (2016).
3. In utero nanoparticle delivery for site-specific genome editing. Nature Communications (2018).
4. Catechol‐Siderophore Mimics Convey Nucleic Acid Therapeutics into Bacteria. Angewandte Chemie International Edition (2024).
5. Peptide Nucleic Acid-Based Biosensors for Cancer Diagnosis. Molecules (2017).
6. Potential of Peptide Nucleic Acids in Future Therapeutic Applications. Advanced Pharmaceutical Bulletin (2018).
7. An introduction to peptide nucleic acid.. Current Issues in Molecular Biology (1999).