Harnessing the programmable nature of DNA to create dynamic nanosystems that interact with biological systems
In the intricate dance of biological systems, cells communicate with breathtaking precision, responding to molecular signals to heal wounds, fight infection, and maintain health. For decades, scientists have sought to master this language to develop smarter therapeutics. DNA nanotechnology is now making this possible, not by altering living cells, but by creating entirely new, synthetic systems that can converse with biology on its own terms.
The key advancement is moving from static structures to dynamic systems that can change their properties in response to specific triggers, much like proteins alter their conformation to mediate function in living organisms 1 2 .
These DNA-controlled systems typically consist of a core nanoparticle surrounded by smaller satellite particles, all held together by DNA linkers. The true magic lies in the DNA "programming," which allows the entire structure to reconfigure itself when it encounters a specific molecular signal, such as a particular DNA sequence or even light.
Static nanoparticles have shown promise in medicine, but they lack the adaptability needed to navigate the complex environment of the human body. Dynamic systems, inspired by nature, offer crucial advantages:
A structure that changes shape in response to a disease-specific biomarker can release its therapeutic payload precisely where and when it is needed.
A single system can be designed to perform multiple sequential tasks, such as navigating to a target cell, entering it, and then activating a specific internal pathway.
A landmark 2016 study published in the journal Science laid the foundation for this field by demonstrating a DNA-controlled dynamic system for mediating cellular interactions 1 2 . Let's break down this crucial experiment.
The researchers designed a core-satellite structure where a central core particle was surrounded by smaller satellite particles. The process involved several key steps:
The satellites were attached to the core using DNA strands that acted as "locks." These linker strands were designed with a toe-hold region—an exposed sequence that acts as an initiation point for a reaction.
The system was programmed to respond to specific "key" DNA strands. When these keys are introduced, they bind to the toe-hold region of the linker DNA.
This binding triggers a process called strand displacement. The key strand systematically displaces the original linker, unzipping the DNA that holds the satellite in place. This causes the satellite to be released from the core.
The freed satellite can then drift away, or the system can be designed to reconfigure into a new, stable arrangement. This transformation is reversible, allowing for complex, life-like cycling between different states.
The experiment yielded two groundbreaking results that highlighted the potential of these dynamic systems:
The researchers engineered the system so that the transformation changed how targeting ligands were displayed on its surface. The "active" configuration made these ligands more accessible to receptors on the target cells. This dynamic display led to a 2.5-fold increase in cellular targeting efficiency compared to a static system 1 2 .
This was a paradigm shift. It proved that a synthetic nanoparticle could be programmed to not just passively interact with a cell, but to actively change its own properties to enhance that interaction, mimicking the adaptive behaviors of natural biological systems.
Subsequent research has continued to validate the importance of dynamic control and structural design. For instance, a 2025 study systematically compared how different DNA nanostructures are internalized by various cell types relevant to tissue engineering 3 . The results clearly show that the physical form of the nanostructure profoundly influences its function.
| Cell Type | 1D Six-Helix Bundle (6HB) | 2D Three-Point Star (3PS) | 3D Tetrahedron (TDN) |
|---|---|---|---|
| Myoblasts (C2C12) | High | High | Low |
| Endothelial Cells (HUVEC) | Moderate | Highest | Low |
| Fibroblasts (HSF) | Highest | Moderate | Low |
| Chondrocytes (SW1353) | Highest | Moderate | Low |
| Osteoblasts (MC3T3-E1) | High | Moderate | Highest |
Data adapted from 3
| Dimension | Example Structure | Key Advantages |
|---|---|---|
| 1D | Six-Helix Bundle (6HB) | Highest mean uptake across cell types; superior stability (95% integrity after 24h) 3 |
| 2D | Three-Point Star (3PS) | Rapid cellular uptake; effective in specific cells like endothelial cells 3 |
| 3D | Tetrahedron (TDN) | Well-defined spatial organization; can mimic complex 3D geometries 3 |
| Experimental Condition | Observed Configuration | Degree of Order |
|---|---|---|
| Lower Ionic Strength | Mix of Triangular Bipyramid and Pyramid shapes | Lower symmetry, more liquid-like |
| Higher Ionic Strength | Convergence toward Triangular Bipyramid | Higher symmetry, more ordered |
| Dynamic Adjustment | Guided assembly toward desired target structure | Controlled, programmable order |
Data summarized from 4
Creating these sophisticated DNA-controlled systems requires a suite of specialized tools and materials. The following components are essential in this field.
| Tool or Material | Function | Specific Example |
|---|---|---|
| Programmable DNA Strands | The fundamental building blocks that self-assemble into desired structures via base-pairing. | Rolling Circle Amplification (RCA) for producing long, repetitive strands 5 . |
| Functional Nucleic Acids (FNAs) | Provide sensing and activity; the "brain" of the system. | Aptamers (for targeting), DNAzymes (catalytic DNA), and toe-hold strands for stimulus-response 5 . |
| Core and Satellite Particles | Form the central scaffold and movable parts of the dynamic system. | Gold nanorods (for light response) 5 , polymer colloids 4 , and emulsion droplets 4 . |
| Stability-Enhancing Reagents | Protect DNA structures from degradation in biological environments. | Magnesium ions (Mg²⁺) to shield the negative charge of the DNA backbone 5 . |
| Characterization Instruments | Measure the size, charge, and stability of the assembled nanostructures. | Acoustic spectrometers for particle size and zeta potential in concentrated dispersions . |
The fundamental building material that enables precise self-assembly of nanostructures through predictable base-pairing rules.
Advanced instrumentation to analyze the size, structure, and stability of assembled DNA nanostructures in various environments.
The journey of DNA nanotechnology from a theoretical concept to a tool for programming cellular interactions is well underway. The pioneering work on dynamic core-satellite systems has paved the way for even more advanced applications.
Recent breakthroughs include the development of fully functional "STARM" artificial cells built entirely from DNA. These systems can be activated by light or ions to present synthetic ligands that engage with receptors on living mammalian cells, guiding processes like tissue formation and regeneration in living animals 5 . This demonstrates a future where injectable, DNA-based artificial cells can work alongside our own to repair damaged tissue and combat disease.
The convergence of programmable nanostructures, dynamic reconfiguration, and a deep understanding of cellular biology is creating a new paradigm in medicine—one where therapies are not merely administered, but intelligently orchestrated.
DNA nanodevices that can navigate to specific cells and release therapeutics only in response to disease biomarkers.
Programmable scaffolds that guide stem cell differentiation and tissue regeneration with unprecedented precision.
DNA-based sensors that can detect multiple disease markers simultaneously and provide real-time monitoring.