Smart nanogels powered by enzymes move through dense tissue by adapting to local conditions, offering a safer and more effective alternative for targeted delivery in complex environments.
(Nanowerk Spotlight) Inside the human body, most therapeutic nanoparticles never reach their destination. They are designed to deliver drugs, genes, or imaging agents, yet they often stall just outside their targets, trapped in mucus, slowed by dense tissue, or immobilized in joint fluid. These barriers, which protect against infection and mechanical stress, also block intervention. Nanoparticles rely on diffusion to move, and in thick biological environments, diffusion alone is not enough.
To get around this, researchers have been trying to give particles the ability to move on their own. One approach is to power them with enzymes by attaching catalytic proteins that convert local fuel, such as urea or hydrogen peroxide, into chemical gradients that push the particle forward. These enzyme-driven nanomotors can move through liquids and even steer through cell interiors. But their design has been limited. Most are built on hard inorganic materials like mesoporous silica, which do not deform or adapt and often require high concentrations of fuel to function. These particles can accumulate in tissue and trigger toxicity. Attempts to clear paths for them by chemically loosening tissue add additional risk.
A more promising strategy is to build nanomotors from soft, tunable materials that respond to their environment in ways that mimic biological tissue. One such material is the nanogel, a flexible polymer network that holds water, changes shape, and breaks down under specific conditions. Nanogels have already been used to deliver drugs through mucus and other difficult tissue barriers. But until now, they have mostly acted as passive carriers. The question has been whether nanogels could be redesigned not just to adapt to their surroundings, but to move through them.
A new study in Advanced Functional Materials (“Smart Nanogels as Enzyme‐Driven Nanomotors for Navigating Viscous Physiological Barriers”) addresses this directly. The research team developed a group of enzyme-powered nanogels that can navigate viscous biological media without disrupting it. These nanogels change size and surface properties in response to changes in temperature, pH, and redox state. They use urea as a fuel source, which is naturally present in the bladder and other tissues. Most importantly, they function without altering the surrounding environment. They do not rely on external triggers or tissue modification. They adapt, respond, and move.
Schematic structure of the NGs (i-iv), as well as their sensitive capacities. The chemical structures of the polymers (p-NIPAM, p-IAc, p-HEMA), and crosslinkers (BIS and BAC). (Image: reprinted from DOI:10.1002/adfm.202510203, CC BY) (click on image to enlarge)
The researchers created four nanogel types using poly(N-isopropylacrylamide), or p-NIPAM, a temperature-sensitive polymer that shrinks above 32 degrees Celsius. They combined it with poly-itaconic acid, or p-IAc, which provides responsiveness to acidity. This combination allowed the nanogels to shrink or swell based on both temperature and pH. In acidic conditions, like those found in tumors or intracellular compartments, the gels contract.
To control the internal structure, they used two different crosslinking agents. One was BIS, a stable linker that provides mechanical strength. The other was BAC, which contains disulfide bonds that can be broken in the presence of glutathione. Because glutathione is more concentrated inside cells and in tumors, this design allows for controlled degradation in those environments.
Two of the nanogels were also given an outer coating of poly(2-hydroxyethyl methacrylate), or p-HEMA. This hydrophilic layer increases water uptake and reduces protein adsorption, making the gels more biocompatible and less likely to trigger immune responses. The result was four distinct nanogel types, each with different combinations of responsiveness, density, and mechanical properties.
The team attached urease enzymes to the surfaces of these nanogels using standard chemical coupling. Urease breaks down urea into ammonia and carbon dioxide, creating a chemical imbalance in the surrounding fluid. This imbalance causes the nanogels to move, a process known as ionic self-diffusiophoresis. In simple terms, the gel generates its own gradient and propels itself through the liquid.
Testing showed that the enzyme successfully anchored to all nanogel types. The gels maintained their shape and size after enzyme attachment. They also remained stable, with no signs of aggregation. Although the enzyme activity was reduced compared to free urease, it remained sufficient to support motion. The researchers designed the attachment to be asymmetric, which is necessary to produce directional propulsion rather than random movement.
Each nanogel was evaluated for how it responded to environmental stimuli. Temperature increases from 35 to 44 degrees Celsius caused the gels to shrink significantly. Acidic conditions also caused contraction, and the redox-sensitive gels degraded in the presence of glutathione. These changes reduced the gels’ size, which is important for slipping through tight or crowded spaces. Gels with a p-HEMA shell showed increased stiffness and slower response, but remained tunable. The design allowed the researchers to fine-tune mechanical properties based on specific needs.
To confirm movement, the researchers tracked individual nanogels under a microscope. They tested different concentrations of urea and compared active nanogels with enzyme-deactivated controls. In the presence of urea, the active gels moved significantly more than the controls. The diffusion coefficient increased with fuel concentration. At 100 millimolar urea, the fastest gels showed a 40 percent increase in motion. Since urea concentrations in urine are typically two to three times higher, these results suggest that the nanogels could operate effectively in real tissues.
The most striking part of the study came when the nanogels were tested in simulated synovial fluid. This dense, viscous fluid is notoriously difficult for particles to move through. Previous designs required either very high fuel concentrations or chemical alteration of the fluid. Here, the enzyme-powered nanogels moved on their own, without altering the fluid’s structure. Even at 25 millimolar urea, the gels spread rapidly through the chamber. At higher concentrations, they moved faster and farther.
The researchers measured how quickly and widely the nanogels spread through the fluid. Without urea, movement was minimal. With increasing fuel, the gels reached a critical point where their spread accelerated, eventually covering the entire visible area. This behavior suggests that the chemical products of the enzyme reaction mix with the fluid in a way that enhances motion. Importantly, none of the nanogels affected the fluid’s elasticity or viscosity, confirming that their movement did not depend on modifying the environment.
Different nanogel types showed different behaviors. Those containing BAC, which makes the structure more compact, moved more efficiently. Core-shell gels with the p-HEMA layer moved more slowly, likely due to their larger size and greater interaction with the surrounding medium. These differences demonstrate how surface properties and internal structure influence collective motion. By adjusting the design, it may be possible to tailor nanomotors for different tissue environments.
The researchers also confirmed that the nanogels were safe. Human dermal fibroblasts maintained high viability after exposure to all gel types, with and without urea. Microscopy showed that the gels were taken up by cells and remained near the nucleus. Spectroscopic analysis showed changes in cell chemistry after exposure, suggesting potential for drug delivery or local modulation of cellular behavior.
This work demonstrates that soft, enzyme-powered nanogels can move autonomously through dense biological media without disrupting it. They adapt to local conditions, use a natural fuel source, and avoid toxicity. Their motion does not depend on altering the tissue or applying external triggers. These features make them promising candidates for drug delivery in tissues where movement is usually limited. The modular design also allows researchers to fine-tune behavior, size, and response properties for different clinical contexts.
By shifting from rigid, inorganic systems to responsive, soft nanogels, this study marks a step forward in how we think about motion at the nanoscale. These materials do not just carry cargo. They behave dynamically, moving and adapting in complex environments where passive particles cannot.
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ORCID information
David Esporran-Ubieto (The Barcelona Institute of Science and Technology)
, 0000-0002-9858-415X first author
Samuel Sanchez (The Barcelona Institute of Science and Technology)
, 0000-0001-9713-9997
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