ASU Study Reveals How Water Can Make Nanomedicine Safer, Smarter

Nanomedicine has long promised cancer treatments and other therapies that hit only diseased cells while sparing healthy tissue. In reality, getting tiny drug-carrying particles to navigate the body’s defenses has proved far more difficult.

Now, researchers at Arizona State University say a missing piece of the puzzle has been hiding in plain sight: water.

In a new experimental study published in the Proceedings of the National Academy of Sciences, an ASU team has directly measured how water molecules interact with the surfaces of coated nanoparticles — and shown that those interactions can help predict how the particles will behave in the body.

“Water is necessary for all life,” lead author Alexandra Navrotsky, a Regents Professor in the School of Molecular Sciences and director of ASU’s Center for Materials of the Universe, said in a news release. “And in medicine, it is the first molecule that interacts with any nanoparticle surface in a biological environment. By directly measuring the energetics of water adsorption, we can quantify the interaction potential of the nanoparticle surface and better predict how it will behave in the body.”

The work offers the first quantitative thermodynamic framework linking water–surface energetics to key aspects of nanoparticle performance, such as stability, immune recognition and drug delivery potential.

Why water at the surface matters

Engineered nanoparticles designed to carry drugs, act as imaging agents or deliver heat to tumors must survive a gauntlet of biological barriers. As soon as they enter blood, gut or brain fluids, they are instantly surrounded by water and a swarm of proteins and other biomolecules.

This microscopic “stew” determines whether nanoparticles clump or stay dispersed, slip past the immune system or get cleared quickly, and ultimately reach their targets or not. Yet despite water’s central role, previous nanomedicine research had not directly measured how strongly water binds to realistic, biomolecule-coated nanoparticles.

The ASU team set out to change that.

Getting to the core of nanoparticle behavior

The researchers focused on core–shell nanocomplexes built around magnetite, an iron oxide commonly used in biomedical applications. Around these cores, they added three different types of coatings that represent major classes of biomolecules:

• A protein (bovine serum albumin), often used as a stand-in for human serum albumin in drug delivery studies.
• A polysaccharide (potato starch), a sugar-based molecule that tends to be water-loving.
• A fatty acid (lauric acid), a lipid that in bulk form does not mix with water.

Using a highly sensitive calorimetry–gas adsorption system, the team measured how much heat was released as water molecules attached to the dry, coated nanoparticles. That allowed them to quantify the energetics of water adsorption, estimate how much of the surface was hydrophilic, or water-attracting, and compare the behavior with free biomolecules and bare magnetite.

Each coating, they found, dramatically reshaped how water interacted with the nanoparticle — and, by extension, how the particle is likely to interact with the body.

Protein coatings: powerful but “patchy”

For the protein-coated particles, the researchers saw the strongest initial interaction with water. The bovine serum albumin (BSA) created highly active binding sites at the nanoparticle surface, boosting the interaction potential compared with uncoated magnetite.

“The protein coating increases the surface interaction potential of the nanocomplex,” added first author Kristina Lilova, an ASU scientist on the study.

But the measurements also revealed that the total amount of water taken up by the BSA-coated particles was lower than for free BSA. That suggests the protein did not fully cover the magnetite, leaving bare patches of the core exposed.

“But the existence of exposed magnetite regions introduces heterogeneity that may promote protein corona formation and immune recognition,” Lilova added.

This kind of surface “patchiness” could make it easier for opsonins — proteins that tag foreign objects for clearance — to latch on, potentially shortening how long the nanoparticles circulate in the bloodstream.

Starch shells: gentle, reversible interactions

The starch-coated nanoparticles behaved very differently. They presented a large hydrophilic surface area, meaning they could interact with a lot of water, but each individual interaction was weaker than for free starch.

Microscopy showed that starch chains formed a dense shell around the magnetite core, which limited how easily outside water molecules could reach the surface. Chemically, some of the starch’s water-binding groups were already tied up binding to the magnetite itself.

Even so, the combination of a broad hydrophilic surface and weaker binding may be an advantage for certain therapies.

“The weaker interaction potential of the starch coating and its relatively large hydrophilic surface area suggest more dynamic and reversible binding,” Lilova added. “This may be beneficial in drug delivery, where mobility along cell membranes and reduced cytotoxicity are desirable.”

Such reversible interactions could allow nanoparticles to move along cell surfaces and exchange cargo without tearing membranes or triggering strong toxic effects.

Fatty acids: a surprising switch to water-loving

Perhaps the most unexpected result came from lauric acid, the fatty acid coating. In its normal crystalline form, lauric acid essentially ignores water — a familiar oil-and-water effect.

On the nanoparticle surface, though, the story changed. The lauric acid molecules reorganized into a partial bilayer structure, somewhat like a simplified version of a cell membrane. That arrangement created a strongly hydrophilic interface that held onto a stable layer of water.

“The fatty acid rearranges into a partial bilayer with very strong hydrophilicity,” added Lilova. “That structure increases stability and may reduce immune activation compared to more hydrophobic surfaces.”

A more stable, hydrated coating could help nanoparticles stay dispersed longer in the bloodstream and avoid being flagged too quickly by the immune system, potentially extending their circulation time.

Toward “Goldilocks” nanomedicine

Across all three coatings, the study shows that hydration energetics — the thermodynamic signature of how water binds — can serve as a powerful design parameter. It reflects not only how water-friendly a surface is, but also how uniform or heterogeneous that surface may be and how it is likely to interact with biological systems.

The researchers suggest that, taken together, these measurements could help build a “Goldilocks” tool for nanoparticle design, guiding scientists toward coatings that are not too sticky or too slippery, but “just right.”

“Our findings show that surface functionalization doesn’t just change chemistry—it fundamentally alters the thermodynamic landscape at the nano-bio interface,” Lilova added. “By understanding primary hydration energetics, we can rationally engineer nanocarriers with tailored stability, immune interactions and drug delivery behavior.”

Navrotsky emphasized that the work lays a rigorous foundation for the next generation of nanomedicine.

“This research provides a thermodynamic foundation for designing nanocarriers with predictable biological reactivity,” she said. “It moves us one step closer to truly rational nanomedicine.”

Looking ahead, the team sees broad applications for their approach, from targeted cancer therapies and imaging contrast agents to biosensors. Future studies will build on this thermodynamic framework to directly measure how different biomolecular coatings stabilize nanocomplexes under more complex, realistic biological conditions.

If successful, such efforts could help turn the long-held vision of nanomedicine into practical treatments: tiny, carefully engineered particles that carry drugs exactly where they are needed, stay in the body just long enough to do their job and then quietly disappear.

Source: Arizona State University