Framework nucleic acids (FNAs) are not only powerful tools in drug discovery but also emerging candidates as direct therapeutic agents. Their unique structural and functional properties enable them to mimic natural biological systems, modulate cellular behavior, and induce targeted physiological responses. One of the most promising applications lies in their ability to function as synthetic membrane channels. Inspired by natural ion channels, DNA origami-based nanopores have been engineered to span lipid bilayers with precise control over pore size and stability. These biomimetic structures facilitate the selective transport of small molecules and folded proteins across membranes, offering potential for intracellular delivery or controlled release strategies.
A landmark study by Langecker et al. demonstrated that synthetic DNA nanopores could stably integrate into lipid bilayers and exhibit predictable electrical properties, enabling real-time monitoring of molecular translocation. Subsequent work by Krishnan et al. expanded this concept by designing large-diameter DNA nanopores capable of transporting macromolecules such as enzymes and antibodies. This capacity opens new avenues for treating diseases involving impaired molecular trafficking, including certain metabolic disorders and neurodegenerative conditions.
In addition to passive transport, FNAs can be gated using external stimuli. Burns et al. developed oligonucleotide-gated DNA nanopores that respond to specific DNA sequences, allowing programmable control over cargo release. Similarly, temperature-, small molecule-, and protein-responsive gating mechanisms have been implemented, enabling on-demand delivery within complex biological environments. These features make FNA-based nanodevices ideal for smart therapeutics where timing and location of action are critical.
Beyond transport, FNAs have shown promise in mimicking enzymatic functions. Ohmann et al. reported a synthetic scramblase built from DNA nanostructures that catalyzes phospholipid flipping between membrane leaflets, exposing phosphatidylserine on the outer surface—a key signal in apoptosis and immune activation. This artificial enzyme operates at an unprecedented rate of 10⁷ lipids per second, demonstrating the potential of nucleic acid frameworks to replicate complex biochemical activities.
Another groundbreaking application involves gene regulation through topologically switchable FNAs. Jiao et al. designed DNA frameworks where the T7 promoter is topologically constrained. Upon stimulation, conformational reconfiguration releases the promoter stress, activating transcription in prokaryotic cells. This dynamic control enables on-demand gene expression, with applications in synthetic biology and bacterial engineering.
Moreover, FNAs can directly influence cell fate without mimicking proteins. Jiang et al. discovered that rectangular DNA origami structures reduce acute kidney injury in mice by promoting renal accumulation and protecting tubular cells, independent of known ligand-receptor interactions. The therapeutic effect was attributed to shape-dependent biodistribution rather than specific targeting, suggesting that geometry alone can trigger beneficial biological outcomes.
Tetrahedral DNA nanostructures (TDNs) also demonstrate intrinsic therapeutic activity.PDI Antibody MedChemExpress Tian et al.SOCS-1 Antibody Epigenetics encapsulated melittin, a potent cytolytic peptide, within conformationally responsive TDNs.PMID:34953369 Upon reaching target cells, the structure undergoes reconfiguration, releasing melittin selectively and inducing pyroptosis-like cell death—particularly effective against tumor cells. This strategy enhances specificity while minimizing off-target toxicity.
Collectively, these findings illustrate that FNAs can act as autonomous, programmable therapeutics. Their ability to mimic channel functions, emulate enzymes, regulate gene expression, and trigger programmed cell death positions them at the forefront of next-generation nanomedicine. With ongoing advances in design and responsiveness, FNAs represent a versatile platform for developing intelligent, self-regulating therapies tailored to complex disease mechanisms.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com