Researchers at Arizona State University have identified hydration energetics as a key factor influencing the performance of nanoparticles in medical applications. Their findings, published in Proceedings of the National Academy of Sciences, focus on how water interactions with nanoparticle surfaces affect their biological behavior.
"Water is necessary for all life," said Alexandra Navrotsky, 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."
The study measured hydration energetics for biomolecule-coated magnetite nanoparticles. Researchers found that different coatings—protein, polysaccharide, or fatty acid—altered how water interacted with these particles and influenced factors such as immune recognition and drug delivery potential.
The team included first author Kristina Lilova, Tamilarasan Subramani, Isabella Montini, Anne Harrison, Manuel Scharrer, Jun Wu and Hongwu Xu. They provided a thermodynamic framework connecting primary water energetics to nanoparticle biological performance.
Nanomedicine has faced challenges due to biological barriers that limit targeted drug delivery. Many treatments distribute drugs throughout the body rather than targeting specific sites like tumors, which can cause side effects.
To address these issues, scientists have explored using nanoparticles as carriers for drugs. However, once inside the body and exposed to fluids such as blood or brain fluid, nanoparticles quickly interact with water molecules and biomolecules that determine their stability and effectiveness.
Previous research had not directly measured how water adsorbs onto biomolecule-coated magnetic nanoparticles. The ASU researchers studied magnetite cores coated with three types of biomolecules: bovine serum albumin (a protein), potato starch (a polysaccharide), and lauric acid (a fatty acid).
Using calorimetry–gas adsorption methods, they measured how each coating affected water uptake and interaction potential compared to uncoated particles or free biomolecules.
Results showed that protein-coated nanoparticles had strong initial interactions with water but lower total uptake than free protein due to incomplete coverage. "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." This could make them more likely to be cleared by immune cells.
Starch-coated particles had a large hydrophilic area but weaker binding strength because starch chains used their hydroxyl groups to bind to magnetite rather than interact with water. Electron microscopy showed a dense shell around these particles. "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."
Lauric acid coatings reorganized into partial bilayers on magnetite surfaces despite being hydrophobic when pure; this increased their ability to interact with water while potentially reducing immune activation. "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."
Across all coatings tested, hydration enthalpy was shown to reflect differences in surface properties relevant for medical use.
"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."
Navrotsky added: "This research provides a thermodynamic foundation for designing nanocarriers with predictable biological reactivity... It moves us one step closer to truly rational nanomedicine."
The work suggests future directions including direct measurements on stabilization effects from other representative biomolecular coatings on similar complexes.
Funding was provided by the U.S. Department of Energy; research took place at Arizona State University's Center for Materials of the Universe under Navrotsky's leadership.
