New study moves nanomedicine one step closer to better and safer drug delivery

(Press-News.org) Researchers at Arizona State University have uncovered a key scientific principle that governs how what’s coated on the surfaces of engineered nanoparticles may ultimately control how they work in our bodies.

 

In a new study published in Proceedings of the National Academy of Sciences, the team directly measured how water interactions influence nanoparticle biological performance.

 

“Water is necessary for all life,” said Navrotsky, the lead author of the study, Regents Professor in the School of Molecular Sciences and director of Arizona State University’s Center for Materials of the Universe. “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.”

 

This so-called hydration energetics were measured for a series of biomolecule-coated magnetite nanoparticles, revealing how different surface coatings alter water interactions, immune recognition and drug delivery potential.

 

The study, led by Navrotsky and ASU scientists including first author Kristina Lilova, Tamilarasan Subramani, Isabella Montini, Anne Harrison, Manuel Scharrer, Jun Wu and Hongwu Xu, provides the first quantitative, thermodynamic framework linking how primary water energetics relate to nanoparticle biological performance.

 

Why water matters

Despite major efforts, the promise of nanomedicine has largely failed to deliver a new generation of better drugs to treat illness and disease. This has been mainly due to the human body, which has provided a formidable maze of barriers and defenses for scientists to overcome to deliver the right drug to the right target at the right time.

 

That’s also why cancer chemotherapy has had its long-known severe side effects, delivering unwanted toxins throughout the body while trying to kill the tumor.

 

Therefore, scientists have been hard at work to develop a Trojan horse type of nanomedicine therapy by surrounding drugs within a protective cage of nanoparticles.

 

But there are huge, unresolved challenges.

 

These nanoparticles, designed for drug delivery, imaging and therapeutic applications must first function in complex biological fluids such as blood, gut or brain fluids after being swallowed. Once introduced into the body, nanoparticles are immediately surrounded by water molecules and biomolecules, forming a nanocomplex stew that dictates their stability, circulation time, immune response and cellular uptake.

 

Despite the central role of hydration in nanomedicine, previous research had not directly measured the energetics of water adsorption on biomolecule-coated magnetic nanoparticles.

 

Getting to the core of the problem

The ASU team addressed this gap by studying core–shell nanocomplexes composed of magnetite (iron oxide) cores coated with three representative biomolecules: a protein (bovine serum albumin), a polysaccharide (potato starch) and a fatty acid (lauric acid).

 

Using a highly sensitive calorimetry–gas adsorption system, the researchers measured the energetics of water adsorption on dry coated nanoparticles, their hydrophilic area and interaction potential, and compared the results to free biomolecules and uncoated magnetite.

 

The results showed that each coating dramatically alters the hydration behavior—and the biological interaction potential of the nanocomplex.

 

Patchy protein power

The first experiment of used a nanoparticle coated with a protein, bovine serum albumin (BSA), commonly used as a model for human serum albumin in drug delivery research. Overall, the protein coating produced the strongest initial interaction with water when coated onto magnetite nanoparticles. The BSA-coated particles exhibited strong binding sites exposed at the surface.

 

However, the total water uptake was lower than that of free BSA, revealing incomplete surface coverage and the presence of uncoated magnetite patches.

 

“The protein coating increases the surface interaction potential of the nanocomplex,” Lilova explained. “But the existence of exposed magnetite regions introduces heterogeneity that may promote protein corona formation and immune recognition.”

 

But such “patchiness” could favor the adsorption of opsonins—proteins that tag foreign particles for immune clearance—potentially reducing circulation lifetime.

 

A starch shell

In contrast, the starch-coated magnetite exhibited a large, water-loving (hydrophilic) surface area, but weaker interaction potential compared to free starch.

 

The researchers found that starch chains bind to the magnetite surface via hydroxyl groups, reducing the number of groups available for water interaction. Transmission electron microscopy revealed a dense encapsulating shell, limiting accessibility to external water molecules.

 

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

 

Such reversible interactions may allow nanoparticles to engage cell membranes without causing significant disruption—an important consideration for biocompatibility.

 

Fatty flavor

Perhaps the most striking finding involved lauric acid, a fatty acid coating. Free crystalline lauric acid does not adsorb water, because as any cook knows, water and fatty oils do not mix.  However, when coated onto magnetite nanoparticles, the fat coating reorganized into a partial bilayer structure, resulting in strong water interaction and a stable hydrated interfacial layer.

 

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

 

The bilayer arrangement may also promote longer circulation times in the body.

 

A better framework for nanomedicine

Across all three coatings, the study establishes that the science of water energetics (hydration enthalpy) can be a key thermodynamic parameter that reflects surface hydrophilicity, heterogeneity and biological interaction potential.

 

The results from the three coating may help the scientists with a “Goldilocks” predictive tool for getting nanoparticle design “just right.”

 

“Our findings show that surface functionalization doesn’t just change chemistry—it fundamentally alters the thermodynamic landscape at the nano-bio interface,” said Lilova.

 

“By understanding primary hydration energetics, we can rationally engineer nanocarriers with tailored stability, immune interactions and drug delivery behavior.”

 

Looking ahead

The work has broad implications for the design of nanomedicines used in applications such as targeted drug delivery, body imaging contrast agents, cancer treatments and biosensing applications.

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

 

As nanomedicine research continues to evolve, hydration energetics may become a central tool in engineering safer, longer circulating and more effective nanoparticle therapies that could one day save lives. The work also provided a stepping stone for future research focused on the direct measurements of the stabilization effect of representative biomolecular coatings on the nanocomplex.

 

The research was supported by the U.S. Department of Energy and conducted at Arizona State University’s Center for Materials of the Universe, led by Navrotksy.

 

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