Nanoparticle coatings’ biological activity revealed by their hydration energetics

Arizona State University researchers have established a thermodynamic framework that links water adsorption on coated magnetite nanoparticles to immune recognition, circulation time and drug delivery potential

Researchers at Arizona State University (ASU), Arizona, USA, have identified a governing scientific principle that determines how surface coatings on engineered nanoparticles influence their behaviour inside the human body. In a recent study the team directly measured how water molecules interact with coated nanoparticle surfaces and demonstrated that these primary hydration energetics can predict biological performance.

“Water is, of course, necessary for all life,” said Dr. Alexandra Navrotsky, Regents Professor in the School of Molecular Sciences and Director of ASU’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,” she said.

The researchers quantified so-called hydration energetics for a series of biomolecule-coated magnetite nanoparticles and showed how distinct surface chemistries alter water interactions, immune recognition and drug delivery potential. The work, led by Navrotsky including colleagues, the first author Dr. Kristina Lilova, Dr. Tamilarasan Subramani, Dr. Jun Wu and Dr. Hongwu Xu, as well as students Isabella Montini, Anne Harrison, Manuel Scharrer. It has provided what the authors describe as the first quantitative thermodynamic framework that links primary water energetics to nanoparticle biological function.

Nanomedicine has long promised to transform drug delivery but despite intense research activity, it has yet to bring forward a broadly realised generation of precision therapeutics. The principal obstacle lies not in the chemistry of the drug but in the biological complexity of the human body. Blood, interstitial fluids and cellular membranes present a labyrinth of barriers that prevent therapeutic agents from reaching their targets at the correct concentration and at the correct time. Conventional chemotherapy illustrates the problem starkly with cytotoxic agents circulating widely, causing damage to healthy tissues and able to produce severe side effects as they attempt to eradicate tumours.

To overcome this challenge, researchers have sought to develop nanoparticle-based ‘Trojan horse’ systems that encapsulate drugs within protective carriers. Once inside the body, however, these carriers encounter an immediate and unavoidable reality. Water molecules and biomolecules surround the nanoparticle surface, form a dynamic interfacial layer and dictate stability, circulation lifetime, immune response and cellular uptake. This interfacial environment – the nano–bio interface – ultimately determine therapeutic outcomes.

Despite the central importance of hydration at this interface, previous studies had not directly measured the energetics of water adsorption on biomolecule-coated magnetic nanoparticles. The ASU team addressed this gap by analysing core–shell nanocomplexes composed of magnetite – an iron oxide – cores coated with three representative biomolecules:

• bovine serum albumin, a protein commonly used as a model for human serum albumin
• potato starch, a polysaccharide
• lauric acid, a fatty acid.

Using a highly sensitive calorimetry–gas adsorption system, the researchers measured the enthalpy of water adsorption on dry coated nanoparticles. They quantified hydrophilic surface area and interaction potential and compared these parameters with those of free biomolecules and uncoated magnetite. The results demonstrated that each surface coating profoundly altered hydration behaviour and therefore biological interaction potential.

In the case of bovine serum albumin-coated nanoparticles, the protein layer produced the strongest initial interaction with water. The coated particles displayed high-energy binding sites at the surface, consistent with exposed functional groups. However, total water uptake remained lower than that of free bovine serum albumin. This discrepancy revealed incomplete surface coverage and the presence of exposed magnetite regions.

“The protein coating increases the surface interaction potential of the nanocomplex,” Lilova said.

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

Such heterogeneity may facilitate the adsorption of opsonins – proteins that tag foreign particles for immune clearance. Enhanced opsonin binding could shorten circulation time and limit therapeutic efficacy. In this context, hydration energetics offered a quantitative explanation for biological vulnerability.

The potato starch-coated magnetite system presented a different profile. The polysaccharide layer produced a relatively large hydrophilic surface area but exhibited weaker interaction potential compared with free starch. The data suggested that starch chains attach to the magnetite surface via hydroxyl groups. This attachment reduces the number of available groups that can interact with water. Transmission electron microscopy revealed a dense encapsulating shell that restricted external water access.

“The weaker interaction potential of the starch coating and its relatively large hydrophilic surface area suggest more dynamic and reversible binding.

“This may be beneficial in drug delivery, where mobility along cell membranes and reduced cytotoxicity are desirable,” Lilova said.

Reversible surface interactions may allow nanoparticles to associate with cell membranes without severe disruption. Such moderation is critical for biocompatibility, particularly in applications that require prolonged circulation.

The most striking result emerged from the lauric acid system. Free crystalline lauric acid does not adsorb water, as lipid and aqueous phases typically segregate. When lauric acid coated magnetite nanoparticles, however, the molecules reorganised into a partial bilayer structure. This rearrangement produced strong water interaction and a stable hydrated interfacial layer.

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

A bilayer-like arrangement may also extend circulation time by shielding the nanoparticle core from immune surveillance. Across all three coating systems, hydration enthalpy emerged as a key thermodynamic descriptor that reflects surface hydrophilicity, heterogeneity and biological interaction potential.

“Our findings show that surface functionalisation does not just change chemistry – it fundamentally alters the thermodynamic landscape at the nano–bio interface. By understanding primary hydration energetics, we can rationally engineer nanocarriers with tailored stability, immune interactions and drug delivery behaviour,” Lilova concluded.

The implications extend beyond drug delivery. Magnetite nanoparticles and related systems could serve as contrast agents for imaging, and as vehicles for targeted cancer therapies and platforms for biosensing. A predictive thermodynamic framework may enable researchers to fine-tune surface chemistry before clinical translation.

As nanomedicine research has continued to evolve, the ability to quantify hydration energetics may become key to design strategies. By measuring the first molecular interaction that any nanoparticle encounters – that with water – scientists can begin to convert empirical trial and error into rational engineering.

For further reading please visit: 10.1073/pnas.2535339123