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Gold nanoparticles are used in an expanding spectrum of biomedical applications. However, little is known about their long-term fate in the organism as it is generally admitted that the inertness of gold nanoparticles prevents their biodegradation. In this work, the biotransformations of gold nanoparticles captured by primary fibroblasts were monitored during up to 6 mo. The combination of electron microscopy imaging and transcriptomics study reveals an unexpected 2-step process of biotransformation. First, there is the degradation of gold nanoparticles, with faster disappearance of the smallest size. This degradation is mediated by NADPH oxidase that produces highly oxidizing reactive oxygen species in the lysosome combined with a cell-protective expression of the nuclear factor, erythroid 2. Second, a gold recrystallization process generates biomineralized nanostructures consisting of 2.5-nm crystalline particles self-assembled into nanoleaves. Metallothioneins are strongly suspected to participate in buildings blocks biomineralization that self-assembles in a process that could be affected by a chelating agent. These degradation products are similar to aurosomes structures revealed 50 y ago in vivo after gold salt therapy. Overall, we bring to light steps in the lifecycle of gold nanoparticles in which cellular pathways are partially shared with ionic gold, revealing a common gold metabolism.

Dezhao Chen,1– 3,* Xiaohan Zheng,2,3,* Qiao Gao,3,4,* Bing Chen,3,5 Yang Sun1,3 1Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Department of Obstetrics & Gynecology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People’s Republic of China; 3Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Obstetrics & Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian Province, People’s Republic of China; 5School of Medical Imaging, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang Sun, Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, People’s Republic of China, Email sunyang@fjmu.edu.cn Bing Chen, Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China, Email BingChen_001@126.com; BingChen_001@fjmu.edu.cnPurpose: Natural ferritin Fn) is a cage-like protein with a central cavity, making it a promising vehicle for drug delivery. However, its non-specific accumulation in iron-metabolizing organs impairs targeting precision and therapeutic efficacy. To overcome this challenge, we aimed to develop a novel biomimetic nanoplatform based on manganese-mineralized ferritin loaded with dihydroartemisinin (DHA@MFn) for precise ovarian cancer treatment, enabling controlled drug release and amplified therapeutic effects within the tumor microenvironment.Methods: We constructed a manganese-mineralized ferritin nanocage encapsulating DHA, resulting in DHA@MFn with favorable physicochemical properties, including a particle size of 12.2 nm and a zeta potential of − 13.54 mV. The stability, stimuli-responsiveness, and in vitro release behavior of DHA@MFn were evaluated under weakly acidic conditions. We assessed its ability to catalyze Fenton-like reactions releasing Mn2+, induce ferroptosis via lipid peroxidation and GSH depletion, and enable controlled drug release. In vivo biodistribution, tumor accumulation, and therapeutic efficacy were investigated using SKOV3 tumor-bearing mice, alone and in combination with irradiation.Results: DHA@MFn remained stable and demonstrated excellent responsiveness to the tumor microenvironment, releasing Mn2+ ions that catalyzed Fenton-like reactions for hydroxyl radical production. The nanoplatform facilitated targeted tumor accumulation and retention, significantly reducing off-target organ distribution, particularly in the liver. The release of DHA induced ferroptosis through lipid peroxidation and GSH depletion, enhancing oxidative stress. Combined with irradiation, DHA@MFn achieved superior tumor ablation through synergistic ferroptosis, photothermal effects, and minimal systemic toxicity compared to free DHA, MFn alone, or their combinations with irradiation.Conclusion: This multifunctional biomimetic nanoplatform presents a promising strategy for precise, multimodal ovarian cancer therapy. By integrating controlled drug delivery, catalytic Fenton-like reactions, and synergistic radiotherapy, DHA@MFn demonstrates significant potential for clinical translation in targeted cancer treatment.Keywords: ferritin, biomineralization, ferroptosis, synergistic therapy, ovarian cancer

Crystallization by particle attachment (CPA) of amorphous precursors has been demonstrated in modern biomineralized skeletons across a broad phylogenetic range of animals. Precisely the same precursors, hydrated (ACC-H₂O) and anhydrous calcium carbonate (ACC), have been observed spectromicroscopically in echinoderms, mollusks, and cnidarians, phyla drawn from the 3 major clades of eumetazoans. Scanning electron microscopy (SEM) here also shows evidence of CPA in tunicate chordates. This is surprising, as species in these clades have no common ancestor that formed a mineralized skeleton and appear to have evolved carbonate biomineralization independently millions of years after their late Neoproterozoic divergence. Here we correlate the occurrence of CPA from ACC precursor particles with nanoparticulate fabric and then use the latter to investigate the antiquity of the former. SEM images of early biominerals from Ediacaran and Cambrian shelly fossils show that these early calcifiers used attachment of ACC particles to form their biominerals. The convergent evolution of biomineral CPA may have been dictated by the same thermodynamics and kinetics as we observe today.

Biomineralization is the process by which organisms produce mineralized tissues. This crucial process makes possible the rigidity and flexibility that the skeleton needs for ambulation and protection of vital organs, and the hardness that teeth require to tear and grind food. The skeleton also serves as a source of mineral in times of short supply, and the intestines absorb and the kidneys reclaim or excrete minerals as needed. This Review focuses on physiological and pathological aspects of the hormonal regulation of biomineralization. We discuss the roles of calcium and inorganic phosphate, dietary intake of minerals and the delicate balance between activators and inhibitors of mineralization. We also highlight the importance of tight regulation of serum concentrations of calcium and phosphate, and the major regulators of biomineralization: parathyroid hormone (PTH), the vitamin D system, vitamin K, fibroblast growth factor 23 (FGF23) and phosphatase enzymes. Finally, we summarize how developmental stresses in the fetus and neonate, and in the mother during pregnancy and lactation, invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization.This Review focuses on physiological and pathological aspects of the hormonal regulation of biomineralization, which is crucial for skeletal health during adulthood, fetal and neonatal development and pregnancy. The role of mineral intake, serum concentrations of mineral and hormonal regulators of biomineralization are highlighted.

Bioavailable calcium is maintained by some crustaceans, in particular freshwater crayfish, by stabilizing amorphous calcium carbonate (ACC) within reservoir organs—gastroliths, readily providing the Ca 2+ needed to build a new exoskeleton. Despite the key scientific and biomedical importance of the in situ molecular-level picture of biogenic ACC and its stabilization in a bioavailable form, its description has eluded efforts to date. Herein, using multinuclear NMR, we accomplish in situ molecular-level characterization of ACC within intact gastroliths of the crayfish Cherax quadricarinatus . In addition to the known CaCO 3 , chitin scaffold and inorganic phosphate (Pi), we identify within the gastrolith two primary metabolites, citrate and phosphoenolpyruvate (PEP) and quantify their abundance by applying solution NMR techniques to the gastrolith “soluble matrix.” The long-standing question on the physico-chemical state of ACC stabilizing, P-bearing moieties within the gastrolith is answered directly by the application of solid state rotational-echo double-resonance (REDOR) and transferred-echo double-resonance (TEDOR) NMR to the intact gastroliths: Pi and PEP are found molecularly dispersed throughout the ACC as a solid solution. Citrate carboxylates are found < 5  Å from a phosphate (intermolecular C⋯P distance), an interaction that must be mediated by Ca 2+ . The high abundance and extensive interactions of these molecules with the ACC matrix identify them as the central constituents stabilizing the bioavailable form of calcium. This study further emphasizes that it is imperative to characterize the intact biogenic CaCO 3 . Solid state NMR spectroscopy is shown to be a robust and accessible means of determining composition, internal structure, and molecular functionality in situ.

The Scaly-foot Snail, Chrysomallon squamiferum , presents a combination of biomineralised features, reminiscent of enigmatic early fossil taxa with complex shells and sclerites such as sachtids, but in a recently-diverged living species which even has iron-infused hard parts. Thus the Scaly-foot Snail is an ideal model to study the genomic mechanisms underlying the evolutionary diversification of biomineralised armour. Here, we present a high-quality whole-genome assembly and tissue-specific transcriptomic data, and show that scale and shell formation in the Scaly-foot Snail employ independent subsets of 25 highly-expressed transcription factors. Comparisons with other lophotrochozoan genomes imply that this biomineralisation toolkit is ancient, though expression patterns differ across major lineages. We suggest that the ability of lophotrochozoan lineages to generate a wide range of hard parts, exemplified by the remarkable morphological disparity in Mollusca, draws on a capacity for dynamic modification of the expression and positioning of toolkit elements across the genome. The Scaly-foot Snail, Chrysomallon squamiferum , is a model for understanding the evolution of biomineralised armour. Here, the authors present a chromosome-level reference genome assembly and tissue-specific transcriptomic data for this enigmatic organism.

Hydroxyapatite (HA) reinforced collagen fibrils serve as the basic building blocks of natural bone and dentin. Mineralization of collagen fibrils play an essential role in ensuring the structural and mechanical functionalities of hard tissues such as bone and dentin. Biomineralization of collagen can be divided into intrafibrillar and extrafibrillar mineralization in terms of HA distribution relative to collagen fibrils. Intrafibrillar mineralization is termed when HA minerals are incorporated within the gap zone of collagen fibrils, while extrafibrillar mineralization refers to the minerals that are formed on the surface of collagen fibrils. However, the mechanisms resulting in these two types of mineralization still remain debatable. In this review, the evolution of both classical and non-classical biomineralization theories is summarized. Different intrafibrillar mineralization mechanisms, including polymer induced liquid precursor (PILP), capillary action, electrostatic attraction, size exclusion, Gibbs-Donnan equilibrium, and interfacial energy guided theories, are discussed. Exemplary strategies to induce biomimetic intrafibrillar mineralization using non-collagenous proteins (NCPs), polymer analogs, small molecules, and fluidic shear stress are discussed, and recent applications of mineralized collagen fibers for bone regeneration and dentin repair are included. Finally, conclusions are drawn on these proposed mechanisms, and the future trend of collagen-based materials for bone regeneration and tooth repair is speculated.

Metal sulfides are a common group of extracellular bacterial biominerals. However, only a few cases of intracellular biomineralization are reported in this group, mostly limited to greigite (Fe3S4) in magnetotactic bacteria. Here, a previously unknown periplasmic biomineralization of copper sulfide produced by the magnetotactic bacterium Desulfamplus magnetovallimortis strain BW‐1, a species known to mineralize greigite (Fe3S4) and magnetite (Fe3O4) in the cytoplasm is reported. BW‐1 produces hundreds of spherical nanoparticles, composed of 1–2 nm substructures of a poorly crystalline hexagonal copper sulfide structure that remains in a thermodynamically unstable state. The particles appear to be surrounded by an organic matrix as found from staining and electron microscopy inspection. Differential proteomics suggests that periplasmic proteins, such as a DegP‐like protein and a heavy metal‐binding protein, could be involved in this biomineralization process. The unexpected periplasmic formation of copper sulfide nanoparticles in BW‐1 reveals previously unknown possibilities for intracellular biomineralization that involves intriguing biological control and holds promise for biological metal recovery in times of copper shortage. Some bacteria have the capability of forming inorganic nanoparticles in a process called biomineralization. A magnetotactic bacterium is shown here, that can precipitate an unknown type of intracellular copper‐based nanoparticles in the periplasm. The biomineral shows peculiar nanometric sub‐structures, and a potential organic envelope surrounding the particles. The protein analysis points toward a new biomineralization mechanism involved in copper detoxification.

Background The ureolytic bacterium Sporosarcina pasteurii is well-known for its capability of microbially induced calcite precipitation (MICP), representing a great potential in constructional engineering and material applications. However, the molecular mechanism for its biomineralization remains unresolved, as few studies were carried out. Results The addition of urea into the culture medium provided an alkaline environment that is suitable for S . pasteurii. As compared to S. pasteurii cultivated without urea , S. pasteurii grown with urea showed faster growth and urease production, better shape, more negative surface charge and higher biomineralization ability. To survive the unfavorable growth environment due to the absence of urea, S. pasteurii up-regulated the expression of genes involved in urease production, ATPase synthesis and flagella, possibly occupying resources that can be deployed for MICP. As compared to non-mineralizing bacteria, S. pasteurii exhibited more negative cell surface charge for binding calcium ions and more robust cell structure as nucleation sites. During MICP process, the genes for ATPase synthesis in S. pasteurii was up-regulated while genes for urease production were unchanged. Interestingly, genes involved in flagella were down-regulated during MICP, which might lead to poor mobility of S. pasteurii. Meanwhile, genes in fatty acid degradation pathway were inhibited to maintain the intact cell structure found in calcite precipitation. Both weak mobility and intact cell structure are advantageous for S . pasteurii to serve as nucleation sites during MICP. Conclusions Four factors are demonstrated to benefit the super performance of S. pasteurii in MICP. First, the good correlation of biomass growth and urease production of S. pasteurii provides sufficient biomass and urease simultaneously for improved biomineralization. Second, the highly negative cell surface charge of S. pasteurii is good for binding calcium ions. Third, the robust cell structure and fourth, the weak mobility, are key for S. pasteurii to be nucleation sites during MICP.

The major mineralized tissues are bone and teeth, which share several mechanisms governing their development and mineralization. This crossover includes the hormones that regulate circulating calcium and phosphate concentrations, and the genes that regulate the differentiation and transdifferentiation of cells. In developing endochondral bone and in developing teeth, parathyroid hormone-related protein (PTHrP) acts in chondrocytes to delay terminal differentiation, thereby increasing the pool of precursor cells. Chondrocytes and (in specific circumstances) pre-odontoblasts can also transdifferentiate into osteoblasts. Moreover, bone and teeth share outcomes when affected by systemic disorders of mineral homeostasis or of the extracellular matrix, and by adverse effects of treatments such as bisphosphonates and fluoride. Unlike bone, teeth have more permanent effects from systemic disorders because they are not remodelled after they are formed. This Review discusses the normal processes of bone and tooth development, followed by disorders that have effects on both bone and teeth, versus disorders that have effects in one without affecting the other. The takeaway message is that bone specialists should know when to screen for dental disorders, just as dental specialists should recognize when a tooth disorder should raise suspicions about a possible underlying bone disorder.Several shared mechanisms govern the development of bone and teeth. This Review summarizes these shared pathways and discusses the disorders that are related to both bone and teeth.