Background

Hydrogels are fundamental in bioengineering, where they serve as scaffolds to support and steer the growth of tissues in-vitro, or in drug delivery where they serve as an excipient to carry drugs to target locations [1,2,3,4,5,6]. Hydrogels are also making inroads in single-cell sequencing [7,8]. In this approach, single cells are encapsulated into droplets with hydrogels beads that bear monoclonal DNA barcodes. After lysis in the droplets, the transcripts from each cell are concatenated to their DNA barcodes, and read out with next-generation sequencing—thus enabling transcriptomics at the single-cell level [9].

In that context, so-called stimuli-responsive gels have become an intense focus of research, as engineers seek to gain control over when, where and how gels can form [4,10,11,12,13,14,15,16,17,18]. Gels that respond to temperature or pH are now common—thanks to the availability of pH or temperature sensitive monomers—and are routinely used to control the timing of gelation (for instance to prevent premature gelation). Gels that respond to other physical stimuli like electrical fields or light have also been reported, thanks to the synthesis of photosensitive monomers or by taking advantage of electrophoretic or electroosmotic effects [19,20,21]. By combining photosensitive gels with lithography, one gains spatial control over the structuration of the gel, and for instance one can imprint a gradient of stiffness (which is known to influence the differentiation of tissues) [22,23]. Electrosensitive hydrogels were embedded in soft robots to control their locomotion with external electrical fields [21,24,25]. However, hydrogels that respond to specific biomarkers (e.g., miRNA, and proteins) have been more elusive, although they would be highly useful for a variety of applications—the most obvious being biosensing [26]. In drug delivery, DNA gels that sense biomarkers for cancers could enhance the specificity of delivery of oncogenic drugs to tumors. In single-cell sequencing, gel beads capable of sensing target transcripts could be used to isolate and sequence particular cellular types or states. Yet the monomers that compose common hydrogels [27,28,29,30,31] (polysaccharide, polyacrylamide, alginate, hyaluronic acid, and polyethylene glycol) are small organic molecules that do not interact naturally with arbitrary nucleic acid or proteins.

DNA gels—which gelify by the mutual hybridization of DNA nanostructures into an extended 3D network—have emerged as a new class of hydrogels with ideal properties for stimuli-responsiveness [32,33,34,35]. In addition to being biocompatible and biodegradable, DNA is an ideal material for interfacing hydrogels with the realm of biomolecules. DNA strands are easily conjugated to polymers such as polyacrylamide or polyethylene glycol, and can sense nucleic acids from biological origins (DNA, mRNA, and miRNA), or small molecules and proteins with the help of aptamers. Additionally, DNA nanotechnology now offers a rich toolbox of nanostructures (e.g., DNA origami [36,37,38]) and mechanisms (strand displacement [26]) to control the shape and dynamics of DNA monomers down to the nanoscale. In the past two decades, a rich library of DNA-based gels has been reported [32,33,34,35,39,40,41,42,43,44,45,46,47], along with numerous applications in sequencing, drug delivery, CTC cell capture or qPCR [26,44,45]. DNA gels that are responsive to pH [32,33,34], temperature [35], or enzymes such as CRISPR-Cas12 [48] have been reported in the literature.

Fabrication of microgels with microfluidics is now well established [49], enabling the generation of spherical microparticles of hydrogels, which are easier to administer in drug delivery [50]. For instance beads of agarose, gelatin or silica were generated with droplets microfluidics [51]. Besides this, research has been done to scale up throughput in view of industrial applications [52,53,54]. For instance, a massively parallel microfluidic device made of Silicon was reported which produces liters of emulsions per hour [52].

DNA gels that change their morphology in response to specific DNA stimuli have been reported [43]. They open avenues for drug delivery, where drugs are loaded and released with controlled swelling and shrinking of the hydrogel. However, the morphological changes were often unidirectional, i.e., were not shown to be reversible [43]. And the demonstration was done on macroscopic DNA gels (mm-cm range), although it would be desirable to achieve the same control on microscopic DNA gels, because they would be easier to inject or inhale [55,56,57,58,59,60,61]. Here, we report DNA microgels that morphologically respond to target DNA strands. We prepare batches of monodisperse microbeads of DNA gels with droplet microfluidics, and actuate morphological changes in the beads with strand displacement, a powerful and general mechanism in DNA nanotechnology [62,63,64,65]. We also demonstrate advanced functionalities, such as selective dissolution of gels, or even a Winner-Takes-All algorithm where two populations of beads mutually dissolve each other until only one population is left. The ease and programmability of implementation opens new avenues, not only for drug delivery, but in other domains such as single-cell sequencing or tissue engineering.

Hydrogels are essential materials in fields ranging from tissue engineering to drug delivery. While traditional smart hydrogels can respond to broad physical or chemical stimuli such as temperature, pH, or light, they typically lack the ability to recognize specific biomolecular signals. In complex biological environments, relying solely on these macroscopic triggers is often insufficient for medical applications that require high precision, such as targeted drug delivery to tumors or single-cell transcriptomics.

To overcome this limitation, there is a strong demand for hydrogels that can be actuated by specific biomolecular stimuli, such as DNA, mRNA, or small molecules. DNA has emerged as an ideal structural material to bridge this gap. Beyond its traditional role as a genetic information carrier, DNA is highly programmable, biocompatible, and capable of precisely recognizing target nucleic acids through base pairing.

By incorporating DNA strands into the hydrogel network, we can utilize strand displacement to physically actuate the gel. This mechanism allows the hydrogel to undergo controlled and reversible morphological changes, such as swelling and shrinking, purely in response to specific DNA inputs. This integration of biomolecular recognition with physical actuation provides a completely new paradigm. It shifts the focus from electronically controlled actuators to autonomous smart materials that can directly sense and react to their local biochemical environment.