Researchers at Arizona State University (ASU) 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 the body.
The team measured the hydration energetics for a series of biomolecule-coated magnetite nanoparticles to investigate how water interactions influence nanoparticle biological performance. Their results revealed how different surface coatings alter water interactions, immune recognition, and drug delivery potential. The study, headed by Alexandra Navrotsky, PhD, Regents Professor in the School of Molecular Sciences and director of Arizona State University’s Center for Materials of the Universe, provides the first quantitative, thermodynamic framework linking how primary water energetics relate to nanoparticle biological performance.
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. “Water is necessary for all life,” said Navrotsky. “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 research provides a thermodynamic foundation for designing nanocarriers with predictable biological reactivity. It moves us one step closer to truly rational nanomedicine.”
First author Navrotsky, together with lead author Kristina Lilova, PhD, and colleagues, reported on their work in PNAS, in a paper titled “Primary biomolecular adsorption energetics of core–shell nanocomplexes: Implications for biological interactions.” In the paper, they concluded that their results “… provide a thermodynamic basis for understanding corona formation, cell membrane interactions, and circulation lifetime, with implications for how primary hydration energetics can affect the behavior of coated inorganic nanocarriers in biological media.”
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 primarily due to the human body’s own formidable maze of barriers and defenses, which scientists need to overcome to deliver the right drug to the right target at the right time.
This is also relevant to why cancer chemotherapy can demonstrate severe side effects, delivering unwanted toxins throughout the body while trying to kill the tumor. One avenue of research for scientists is developing a Trojan horse type of nanomedicine therapy by surrounding drugs within a protective cage of nanoparticles. However, there are huge, unresolved challenges.
Nanoparticles designed for drug delivery, imaging, and therapeutic applications must function in complex biological fluids such as blood, gut, or brain fluids. 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.
“The immune interactions and drug delivery performance of the engineered nanocarriers depend critically on their interactions with biological systems, posing a central and unresolved challenge in nanomedicine,” the authors wrote. “Molecular organization at the nano-bio interface governing the colloidal stability, reactivity, immune recognition, and drug delivery performance of nanoparticles remains difficult to predict.” Understanding the fundamental interactions between nanoparticles and physiological environments, including blood, interstitial fluid, and cellular cytoplasm, has thus become “a major focus of nanomedicine.”
Despite the central role of hydration in nanomedicine, previous research had not directly measured the energetics of water adsorption on biomolecule-coated magnetic nanoparticles. “Quantifying the primary hydration energetics of biomolecule-coated nanomaterials can determine those interactions and provide a basis for engineered nanocarriers with tailored behavior in biological systems,” the investigators further noted.
The ASU team addressed this gap by studying core–shell nanocomplexes composed of magnetite (iron oxide; Fe3O4) cores coated with one of three representative biomolecules: a protein (bovine serum albumin; BSA), a polysaccharide (potato starch), or a fatty acid (lauric acid). Magnetite was selected as the inorganic core in the core–shell nanocomplexes because its biocompatibility, stability, and magnetic properties mean it is already used widely in biomedical applications, including drug delivery and imaging, the authors explained.
The three natural biomolecules selected as surface coatings are commonly used in drug delivery to improve colloidal stability, tune biological interactions, and drug conjugation, the team further pointed out. However, they noted, “Despite the extensive use of such coatings, little is known about how they influence the energetics of the interfacial hydration, which ultimately governs the stability, reactivity, and biological interactions of nanocarriers.”
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.
The first experiment used a nanoparticle coated with the protein bovine serum albumin, which is commonly used as a model for human serum albumin in drug delivery research. The team found that 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. “Bovine serum albumin coating increases the interaction potential of the surface of the nanocomplex in comparison with free BSA but decreases the amount of total water uptake due to a smaller hydrophilic area and the existence of uncoated patches, which can affect the opsonization and the immune response,” the team stated.
“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.”
In contrast, the starch-coated magnetite exhibited a large, water-loving (hydrophilic) surface area, but a 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 the relatively large hydrophilic surface area allow dynamic and reversible binding to biomembranes, thus being beneficial for drug delivery applications,” they reported.
“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 may allow nanoparticles to engage cell membranes without causing significant disruption—an important consideration for biocompatibility.
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 hydrophobic lauric acid coated on nanoparticles rearranges into a partial hydrated bilayer with very strong interaction potential with polar solvents, which increases the nanocomplex stability and circulation time in aqueous media,” the investigators noted.
“The fatty acid rearranges into a partial bilayer with very strong hydrophilicity,” Lilova stated. “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.
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 coatings 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.”
As nanomedicine research continues to evolve, hydration energetics may become a central tool in engineering safer, longer-circulating, and more effective nanoparticles. In their paper the team stated, “These results lead to fundamental insights into how the energetics of primary surface hydration can predict the nanoparticle behavior and interactions in biological media and provide a basis for engineered nanocarriers with tailored colloidal stability, immune interactions, and drug delivery behavior … This work also provides a stepping stone for a consequent paper focused on the direct measurements of the stabilization effect of representative biomolecular coatings on the nanocomplex.”