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NASA NTRS1990

A biosensor for cadmium based on bioconvective patterns

An 'in vitro' method for monitoring cadmium, one of the most lethal bivalent heavy metals, can detect biologically active levels. The effects of cadmium tend to concentrate in protozoa far above natural levels and therein begin transferring through freshwater food chains to animals and humans. In a small sample volume (approximately 5 ml) the method uses the toxic response to the protozoa, Tetrahymena pyriformis, to cadmium. The assay relies on macroscopic bioconvective patterns to measure the toxic response, giving a sensitivity better than 1 micro-g/1 and a toxicity threshold to 7 micro-g/1 for Cd(2+). Cadmium hinders pattern formation in a dose-dependent manner. Arrested organism growth arises from slowed division and mutation to non-dividing classes. Unlike previous efforts, this method can be performed in a shallow flow device and does not require electronic or chemical analyses to monitor toxicity.

Noever, David A.↗

DOE OSTI2024

Combatting melioidosis with chemical synthetic lethality

Burkholderia thailandensishas emerged as a nonpathogenic surrogate forBurkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome ofB. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential forB. thailandensisin the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and β-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity againstB. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.

Science & Technology - Other Topics↗

NASA NTRS2010

Ocular Toxicity Testing of Lunar Dust

This slide presentation reviews the use of ocular testing to determine the toxicity of lunar dust. The OECD recommendations are reviewed. With these recommendations in mind the test methodology was to use EpiOcular, tissues derived from normal human epidermal keratinocytes, the cells of which have been differentiated on cell culture inserts to form a multi-layered structure, which closely parallels the corneal epithelium and to dose the tissue with 100 mg dust from various sources. The in-vitro study provides evidence that lunar dust is not severely corrosive or irritating, however, in vitro tests have limitations, and in vivo tests provides a more complete scenario, and information, it is recommended that in vivo tests be performed.

Meyers, Valerie E.↗

NASA NTRS2019

Cardiopulmonary Inflammatory Response to Meteorite Dust Exposures - Implications for Human Health on Earth and Beyond

This year marks the 50th anniversary of Apollo 11, the first time humans set foot on the Moon. The Apollo missions not only help answer questions related to our solar system, they also highlight many hazards associated with human space travel. One major concern is the effect of extraterrestrial dust on astronaut health. In an effort to expand upon previous work indicating lunar dust is respirable and reactive, the authors initiated an extensive study evaluating the role of a particulate’s innate geochemical features (e.g., bulk chemistry, internal composition, morphology, size, and reactivity) in generating adverse toxicological responses in vitro and in vivo. To allow for a broader planetary and geochemical assessment, seven samples were evaluated: six meteorites from either the Moon, Mars, or Asteroid 4 Vesta and a terrestrial basalt analogue. Even with the relatively small geochemical differences (all samples basaltic in nature), significant difference in cardiopulmonary inflammatory markers developed in both single exposure and multiple exposure studies. More specifically: 1) the single exposure studies reveal relationships between toxicity and a meteorite sample’s origin, its pre-ejected state (weathered versus un-weathered), and geochemical features (e.g. bulk iron content) and 2) multiple exposure studies reveal a correlation with particle derived reactive oxygen species (ROS) formation and neutrophil infiltration. Extended human exploration will further increase the probability of inadvertent and repeated exposures to extraterrestrial dusts. This comprehensive dataset allows for not only the toxicological evaluation of extraterrestrial materials but also clarifies important correlations between geochemistry and health. The utilization of an array of extraterrestrial samples from Moon, Mars, and asteroid 4Vesta will enable the development of a geochemical based toxicological hazard model that can be used for: 1) mission planning, 2) rapid risk assessment in cases of unexpected exposures, and 3) evaluation of the efficacy of various in situ techniques in gauging surface dust toxicity. Furthermore, by better understanding the importance of geochemical features on exposure related health outcomes in space, it is possible to better understand of the deleterious nature of dust exposure on Earth.

Harrington, A. D.↗

NASA NTRS1992

Thermal degradation events as health hazards - Particle vs gas phase effects, mechanistic studies with particles

Experiments on animal subjects are performed to demonstrate that significant lung injury can result from the inhalation of ultrafine TiO2 or Al2O3 particles. The methods include intratracheal instillation of particles, long-term inhalation of particles, and in vitro studies of alveolar macrophages (AMs) to study the production of fibroplast growth factors. The ultrafine TiO2 particles are shown to induce more acute inflammatory reactions than larger particles and lead to persistent chronic effects in the AM-mediated clearance function of particles. The ultrafine particles also induce cytokines more readily, and the data generally suggests that the occurrence of such particles in thermal degradation events makes the fumes highly toxic. The exposure to thermal degradation products is therefore a critical concern for manned space missions with potentially degradable plastic products.

Oberdoerster, G.↗

NASA NTRS1992

More Genetic Engineering With Cloned Hemoglobin Genes

Cells modified to enhance growth and production of proteins. Method for enhancing both growth of micro-organisms in vitro and production of various proteins or metalbolites in these micro-organisms provides for incorporation of selected chromosomal or extrachormosomal deoxyribonucleic acid (DNA) sequences into micro-organisms from other cells or from artificial sources. Incorporated DNA includes parts encoding desired product(s) or characteristic(s) of cells and parts that control expression of productor characteristic-encoding parts in response to variations in environment. Extended method enables increased research into growth of organisms in oxygen-poor environments. Industrial applications found in enhancement of processing steps requiring oxygen in fermentation, enzymatic degradation, treatment of wastes containing toxic chemicals, brewing, and some oxidative chemical reactions.

Bailey, James E.↗

NASA NTRS2019

Oil Dispersant Corexit 9500 Is Weakly Estrogenic, but Does Not Skew the Sex Ratio in Alligator Mississippiensis

During the Deepwater Horizon oil spill, vast quantities of the chemical dispersant Corexit 9500 were applied in remediation efforts. In addition to the acute toxicity and obesogenicity of Corexit, it is important to further evaluate Corexit with long-term sublethal endocrine endpoints. The American alligator (Alligator mississippiensis) exhibits temperature-dependent sex determination, in which egg incubation temperatures during a thermosensitive period (TSP) in embryonic development determine sex of the embryos. Estrogen signals also play critical roles in this process. For example, a single exposure to exogenous estrogen during the TSP overrides the effects of temperature and leads to skewed sex ratios. At a dose of 100 ppm, Corexit significantly induced transcriptional activity of both alligator nuclear estrogen receptors 1 and 2 in vitro using the reporter gene assays. To investigate the estrogenic effects on gonadal development in ovo, alligator eggs were exposed to Corexit at environmentally relevant concentrations (0.25, 2.5, and 25 ppm) prior to the TSP. Significant delays in the hatching and growth were observed in 0.25 and 25 ppm Corexit exposed groups. At one week of age, no significant effects on sex ratios or testicular mRNA abundance were observed as a result of exposure to Corexit at the tested exposure levels, suggesting Corexit does not have strong estrogenic activity in ovo. Further investigations are required using individual components of Corexit to better understand their estrogenic effects on the development and reproductive health of alligators and other coastal aquatic wildlife.

Nicole Mcnabb↗

NASA NTRS1986

Polyamine metabolism and osmotic stress. I. Relation to protoplast viability

Cereal leaves subjected to the osmotica routinely used for protoplast isolation show a rapid increase in arginine decarboxylase activity, a massive accumulation of putrescine, and slow conversion of putrescine to the higher polyamines, spermidine and spermine (HE Flores, AW Galston 1984 Plant Physiol 75: 102). Mesophyll protoplasts from these leaves, which have a high putrescine:polyamine ratio, do not undergo sustained division. By contrast, in Nicotiana, Capsicum, Datura, Trigonella, and Vigna, dicot genera that readily regenerate plants from mesophyll protoplasts, the response of leaves to osmotic stress is opposite to that in cereals. Putrescine titer as well as arginine and ornithine decarboxylase activities decline in these osmotically stressed dicot leaves, while spermidine and spermine titers increase. Thus, the putrescine:polyamine ratio in Vigna protoplasts, which divide readily, is 4-fold lower than in oat protoplasts, which divide poorly. We suggest that this differing response of polyamine metabolism to osmotic stress may account in part for the failure of cereal mesophyll protoplasts to develop readily in vitro.

Non-NASA Center↗

DOE OSTI2024

Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy

T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

A Sensitive Electrochemical Cholinesterase-Inhibiting Biosensor for Organophosphorus Pesticides Based on Ti 3 C 2 TX MXene Quantum Dots

Organophosphorus pesticides (OPs) pose significant environmental and health risks due to their widespread use and toxicity, primarily by inhibiting acetylcholinesterase. Traditional detection methods are often slow and costly, highlighting the urgent need for advanced, sensitive, and accessible technologies. This study developed a highly sensitive electrochemical cholinesterase-inhibiting biosensor for OP pesticides, utilizing Ti 3 C 2 T x MXene Quantum Dots (MQDs), which was synthesized via a hydrothermal method. The biosensor’s performance was characterized using electrochemical impedance spectroscopy, differential pulse voltammetry (DPV), and cyclic voltammetry. DPV proved to be the optimal technique, exhibiting an ultralow detection limit of 1 × 10 −17 M and a wide linear range (10 −14 –10 −8 M) for chlorpyrifos (a model OP) with an estimated inhibition constant of 62 nM. The biosensor demonstrated high selectivity for OPs (chlorpyrifos, acephate, glyphosate) over a non-target pyrethroid (permethrin), confirmed by distinct electrochemical signatures and compared to in vitro cholinergic activity assays in bean beetle homogenates. The enhanced performance is attributed to the high surface-to-volume ratio, quantum confinement effects, and superior conductivity of the MQDs, as well as the robust enzyme immobilization facilitated by glutaraldehyde cross-linking and a chitosan matrix. This work presents a promising platform for rapid, sensitive, and selective detection of OP pesticides, with potential applications in environmental monitoring and public health protection.

Chemistry↗

NASA NTRS1989

Ethylene-associated phase change from juvenile to mature phenotype of daylily (Hemerocallis) in vitro

Hemerocallis plantlets maintained in vitro for extended periods of time in tightly closed culture vessels frequently show a phenotype, albeit on a miniaturized scale, typical of more mature, field-grown plants. The positive relationship of elevated ethylene in the headspace of such vessels to the phase shift from juvenile to mature form is established. Rigorous restriction in air exchange with the external environment by means of silicone grease seals hastens the phase change and improves uniformity of response. Although some plantlets may take longer to accumulate enough ethylene in sealed jars to undergo change, added ethylene and ethylene-releasing agents promote it. Ethylene adsorbants (e.g. mercuric perchlorate) block the shift of juvenile to mature form. Critical ambient ethylene level for the shift is ca 1 microliter l-1. Levels up to 1000 microliters l-1 do not hasten the response but are not toxic. The phase change is fully reversible when air exchange permits ethylene to drop below 1 microliter l-1. At least 1 microliter l-1 ethylene is required to sustain the mature phenotype. The ethylene synthesis inhibitor aminoethoxyvinylglycine (AVG) prevents the phase change, while the ethylene biosynthesis intermediate 1-aminocyclopropanecarboxylic acid (ACC) improves it. KOH, as a CO2 absorbent, does not prevent the phase change. Histology sections demonstrate subtle changes in the form of shoot tips of plantlets undergoing phase change.

NASA Discipline Plant Biology↗

NASA NTRS2018

Physical and Biological Properties of Cobalt- and Copper-Doped Calcium Phosphates as Bone Substitute Materials

Arthritis, osteoporosis, and other bone diseases and defects are common medical issues worldwide. By utilizing ceramic biomaterials as bone substitutes to treat these diseases, bone regeneration can be promoted and toxicity from the substitute material can be limited. Calcium phosphate (CaP) ceramics have become popular as bone substitutes due to their biocompatibility and similarity in composition to natural bone. The purpose of this research was to investigate the physical properties and biological responses of CaP-based bone substitutes, doped with metal ions. Some metal ions are present in natural bone in small amounts, and recent studies show they affect the biological responses of CaPs significantly. Dopants such as magnesium (Mg), strontium (Sr), silicon (Si) and iron (Fe) alter the phase composition, mechanical properties, osteogenesis and angiogenesis properties of CaPs, depending on their concentration and method of addition. In the present study, the effects of cobalt (Co) and copper (Cu) on the physical and biological properties of two main CaP materials, brushite cement (BrC) and tricalcium phosphate (TCP), have been investigated. Different concentrations of dopants in forms of oxide and/or chloride were selected and their effect on phase composition, sintering behavior, density, setting time, compressive strength and in vitro interaction with osteosarcoma and osteoblast cells were studied. Different techniques of sample preparation, challenges during cement preparation and compact sample pressing, sintering, and methods of dopant addition are discussed. The presence of Cu in tricalcium phosphate was found to increase thermal stability of the material and decrease the impact of sintering temperature on porosity. In addition, Cu caused a reduction in expression of inflammatory gene markers by human osteoblast cells and an increased expression at early time points due of osteoinductive markers.The addition of Cu and Co to brushite cement caused an increase in thermal stability of the material, and the addition of Cu caused significant increase in setting time. Small dopant amounts of Co caused decrease in setting time, but higher amounts caused an increase. In addition, Cu dopant in small amounts resulted in an increase of compressive strength. Both Cu and Co led to a decrease in expression of inflammatory gene markers by osteoblast and osteosarcoma cells respectively, and Cu also caused an increase in osteoinductive marker expression. Thus, these results indicate that Cu and Co have a positive impact on the physical, mechanical and biological properties of calcium phosphate biomaterials.

Cummings, Haley V.↗

NASA NTRS1990

Immunological characterization of plant ornithine transcarbamylases

Pea (Pisum sativum L.) ornithine transcarbamylase (OTC) antisera were used to investigate the immunological relatedness of several plant and animal OTC enzymes. The antisera immunoprecipitated OTC activity in all monocot and dicot species tested, and sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of immunoprecipitated protein revealed monomeric proteins ranging from 35,200 to 36,800 daltons in size. Pea OTC antisera did not recognize mammalian OTC protein. OTC activity and protein levels detected on sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblots from homogenates of green leaf, etiolated epicotyl and cotyledon, and root tissues of pea were poorly correlated. This might result from differences in amounts of enzymatically active OTC protein in the homogenates. Alternatively, the antisera may fail to recognize different isozyme forms of OTC, which have been reported for some plant species. A putative cytosolic precursor OTC (pOTC) polypeptide exhibiting and Mr = 39,500 to 40,000 daltons was immunoprecipitated from in vitro translation mixtures of total pea leaf poly(A)+ RNA. The size of the pOTC polypeptide, as compared with mature OTC monomer (36,000 daltons), suggests that a 4 kilodalton N-terminal leader sequence, like that responsible for mitochondrial targeting of the mammalian enzyme, may be involved in organellar import of the plant enzyme.

NASA Discipline Plant Biology↗

DOE OSTI2025

Phenotypically anchored transcriptomics across diverse agrichemicals reveals conserved pathways and unique gene expression signatures in zebrafish

Agrichemicals such as herbicides, fungicides, insecticides, and biocides are widely used in agriculture, yet some are associated with adverse effects in humans and the environment. While many of these chemicals have been extensively studied in vitro and are included in the EPA’s ToxCast program, comprehensive in vivo comparisons using RNA sequencing across structurally diverse agrichemicals, in a single screening platform, are lacking. In this study, we examined structurally diverse agrichemicals found in the U.S. Environmental Protection Agency’s (EPA) Toxcast Phase I and II library by statically exposing early life stage zebrafish at 6 h post fertilization (hpf) until 120 hpf at concentrations ranging from 0.25 to 100 µM. Morphological outcomes were assessed at 120 hpf across 10 endpoints, including yolk sac edema, craniofacial malformations, and axis abnormalities. Chemicals that produced robust concentration-response relationships were selected for transcriptomic profiling. For transcriptomic analysis, zebrafish were statically exposed to each chemical and sampled at 48 hpf, prior to the onset of morphological effects observed at 120 hpf. Differential expression analysis identified between 0 and 4,538 differentially expressed genes (DEGs) per chemical, with no clear correlation to morphological severity. Both DEG and co-expression network analyses revealed chemical-specific expression patterns that converged on shared biological pathways, including neurodevelopment and cytoskeletal organization. Key regulatory genes such as mylpfa and krt4 were identified within co-expression modules, suggesting their potential role in conserved toxicity mechanisms. Semantic similarity analysis of enriched gene ontology (GO) terms, when compared to existing datasets, highlighted gaps in the annotation of neurodevelopmental processes, indicating that some in vivo effects may not be fully captured by current curated resources. The results provide new insights into the modes of action of diverse agrichemicals and establish a framework for understanding how agrichemical structure relates to biological function in a vertebrate model.

agrichemical↗

DOE OSTI2025

Self-Assembly of Accumulated Sphingolipids into Cytotoxic Fibrils in Globoid Cell Leukodystrophy and Their Inhibition by Small Molecules In Vitro

Globoid cell leukodystrophy (GLD) is a rare hereditary inborn error of metabolism due to recessive mutations that cause loss of function of the enzyme galactosylceramidase (GALC). This results in the accumulation of the sphingolipids galactosylceramide (GalCer) and galactosylsphingosine (GalSph) in the lysosomes of neuronal cells. The accumulated GalCer and GalSph in cerebral macrophages of GLD patients are neurotoxic to oligodendrocytes and Schwann cells, leading to demyelination in the nervous system. The disease typically presents with infantile onset in the first six months of life and death by age 2. Here, we identified a supramolecular structure of GalCer and GalSph that may contribute to GLD pathology. Using biophysical assays commonly used for studying proteinaceous amyloids, e.g., amyloidspecific dyes, microscopical imaging, and a series of analytical methods (FTIR, PXRD, and SAXS), we demonstrate that both GalCer and GalSph can self-assemble in vitro into highly organized fibrils reminiscent of fibrils of amyloidogenic proteins. These fibrils exhibit significant cytotoxicity to both neuronal and oligodendroglial cells. Using an inhibitor of the GALC enzyme in cell culture to mimic the GLD pathophysiology, we could detect the accumulation of these fibrils in cells. We also observed that small molecules, which are bona fide inhibitors of proteinaceous amyloids, effectively mitigated the formation of the GalCer and GalSph fibrillar structures in vitro. Finally, the small molecule ameliorated the cytotoxic effects of the sphingolipid fibrils in SH-SY5Y cells, suggesting a potential avenue for therapeutic intervention in GLD orphan disease.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1999

Site-directed mutagenesis of serine 158 demonstrates its role in spinach leaf sucrose-phosphate synthase modulation

Site-directed mutagenesis of spinach sucrose-phosphate synthase (SPS) was performed to investigate the role of Ser158 in the modulation of spinach leaf SPS. Tobacco plants expressing the spinach wild-type (WT), S158A, S158T and S157F/S158E SPS transgenes were produced. Expression of transgenes appeared not to reduce expression of the tobacco host SPS. SPS activity in the WT and the S158T SPS transgenics showed light/dark modulation, whereas the S158A and S157F/S158E mutants were not similarly light/dark modulated: the S158A mutant enzyme was not inactivated in the dark, and the S157F/S158E was not activated in the light. The inability to modulate the activity of the S158A mutant enzyme by protein phosphorylation was demonstrated in vitro. The WT spinach enzyme immunopurified from dark transgenic tobacco leaves had a low initial activation state, and could be activated by PP2A and subsequently inactivated by SPS-kinase plus ATP. Rapid purification of the S158A mutant enzyme from dark leaves of transgenic plants using spinach-specific monoclonal antibodies yielded enzyme that had a high initial activation state, and pre-incubation with leaf PP2A or ATP plus SPS-kinase (the PKIII enzyme) caused little modulation of activity. The results demonstrate the regulatory significance of Ser158 as the major site responsible for dark inactivation of spinach SPS in vivo, and indicate that the significance of phosphorylation is the introduction of a negative charge at the Ser158 position.

Non-NASA Center↗

NASA NTRS1985

In vivo inhibition of polyamine biosynthesis and growth in tobacco ovary tissues

Post fertilization growth of tobacco ovary tissues treated with inhibitors of polyamine (PA) biosynthesis was examined in relation to endogenous PA titers and the activities of arginine decarboxylase (ADC, EC 4.1.1.19) and ornithine decarboxylase (ODC, EC 4.1.1.17). DL-alpha-Difluoromethylornithine (DFMO) and DL-alpha-difluoromethylarginine (DFMA), specific, irreversible ("suicide") inhibitors of ODC and ADC in vitro, were used to modulate PA biosynthesis in excised flowers. ODC represented >99% of the total decarboxylase activity in tobacco ovaries. In vivo inhibition of ODC with DFMO resulted in a significant decrease in PA titers, ovary fresh weight and protein content. Simultaneous inhibition of both decarboxylases by DFMO and DFMA produced only a marginally greater depression in growth and PA titers, indicating that ODC activity is rate-limiting for PA biosynthesis in these tissues. Paradoxically, DFMA alone inhibited PA biosynthesis, not as a result of a specific inhibition of ADC, but primarily through the inactivation of ODC. In vivo inhibition of ODC by DFMA appears to result from arginase-mediated hydrolysis of this inhibitor to urea and DFMO, the suicide substrate for ODC. Putrescine conjugates in tobacco appear to function as a storage form of this amine which, upon hydrolysis, may contribute to Put homeostasis during growth.

NASA Program Space Biology↗

DOE OSTI2025

From Structure to Function: Zn/Mn-Modified Maghemite as an Advanced Nanoplatform for Magnetic Hyperthermia and Radionuclide Therapy

The development of nanoplatforms capable of efficient heat generation and stable radionuclide delivery is essential for effective bimodal cancer therapy. Here, in this study, binary (Fe–M) and ternary (Fe–M–M′) metal oxide nanoparticles were synthesized via a polyol method optimized to produce flower-like γ-Fe 2 O 3 (maghemite) structures, with M and M′ representing Zn and/or Mn. Comprehensive structural and magnetic characterization was conducted to explain the relationship between composition, defect structure, and hyperthermic performance. The analyses revealed that cation substitution induced an Fe-site vacancy, primarily at octahedral positions, leading to local structural distortions, as confirmed by powder X-ray diffraction and pair distribution function analysis. The optimized composition, with Zn/Mn/Fe = 0.040:0.182:1, exhibited the highest concentration of vacancies and structural disorder. These vacancies altered the bonding environment, enhancing magnetic interactions at tetrahedral sites while weakening those at the octahedral positions. The resulting multicore nanoflowers (20–63 nm; core size 13–18 nm) displayed strong heating performance, with intrinsic loss power ranging from 0.34 to 5.77 nHm 2 kg –1 . The optimized sample achieved a temperature increase of 30 °C within 2 min and a specific absorption rate of 369 W g –1 . This composition was further coated with citrate (CA) and successfully radiolabeled with 177 Lu, achieving a radiolabeling yield of 92.7% and excellent stability, thus forming a robust nanoplatform for combined magnetic hyperthermia and radionuclide therapy. Biological evaluation of the optimized S5 composition revealed selective cytotoxicity toward HeLa and LS174 cells, while toxicity was significantly lower to A549, A375, and normal MRC-5 cells. Citrate coating of S5 nanoparticles (S5@CA) drastically reduced their cytotoxicity across all tested cell lines (IC 50 > 200 μg mL –1 ), confirming their enhanced biocompatibility for therapeutic applications. In HeLa cells subjected to magnetic hyperthermia, the viability decreased to approximately 84% after 30 min and 61% after 60 min of treatment, demonstrating the sustained hyperthermic effect at a controlled working temperature of 48 °C. These results underscore the effectiveness of cation substitution and vacancy engineering in tailoring the functional properties of maghemite-based nanomaterials for advanced multimodal cancer therapies.

36 MATERIALS SCIENCE↗