Expanding from materials to biology inspired by biomineralization

Biomineralization is the intricate process by which living organisms orchestrate the formation of organic–inorganic composites by regulating the nucleation, orientation, growth, and assembly of inorganic minerals. As our comprehension of biomineralization principles deepens, novel strategies for fabricating inorganic materials based on these principles have emerged. Researchers can also harness biomineralization strategies to tackle challenges in both materials' science and biomedical fields, demonstrating a thriving research field. This review begins by introducing the concept of biomineralization and subsequently shifts its focus to a recently discovered chemical concept: inorganic ionic oligomers and their cross‐linking. As a novel approach for constructing inorganic materials, the inorganic ionic oligomer‐based strategy finds applications in biomimetic regeneration and repair of hard tissues, such as teeth and bones. Aside from innovative methods for material fabrication, biomineralization has emerged as an alternative method for tackling biomedical challenges by integrating materials with biological organisms, facilitating advancements in biomedical fields. Emerging material‐biological integrators play a critical role in areas like vaccine improvement, cancer therapy, universal blood transfusion, and arthritis treatment. This review highlights the profound impact of biomineralization in the development and design of high‐performance materials that go beyond traditional disciplinary boundaries, potentially promoting breakthroughs in materials science, chemical biology, biomedical, and numerous other domains.


| INTRODUCTION
Biomineralization refers to the process by which organic living organisms regulate the formation of inorganic minerals, and it is a widespread phenomenon in nature. [1]s early as 3.5 billion years ago, from prokaryotes to eukaryotes, organisms have gradually developed the ability to synthesize minerals, and through the body of genes to regulate the operation of the mineralization "program," to achieve the regulation of their own metabolic processes, to adapt to changes in the environment and biological stress. [2,3]In recent years, with the continuous expansion of the field of biomineralization, researchers through the simulation of the biomineralization process, the use of biological macromolecules of the template effect on the reaction kinetics of inorganic nucleation-crystallization process to control, can realize the controlled synthesis of biomimetic materials, to build excellent performance of organic-inorganic composite materials.Biomimetic materials exhibit marvelous properties by virtue of their hierarchically ordered structures on multiple length scales, and play an important role in chemistry, materials science and biomedicine.For example, a bionic material with good ultimate strength and fracture toughness was developed by freeze-induced assembly and acetylation processes to obtain a β-chitin matrix, mineralization of the matrix by decomposition of Ca(HCO 3 ) 2 , and then infiltration of fibroin and a hot pressing process, with which the chemical composition, hierarchical structure and mechanical properties of nacre-like materials are highly analogous with natural nacre [4] ; for the restoration of bone defects [5] and dental enamel, [6] the restorative solution can be added with the addition of proteins or peptides to achieve control of the nucleation, growth, and orientation processes of hydroxyapatite (HAP), in situ remineralization of crystals, and preparation of inorganic bionic restorative layers with excellent mechanical strength and friction properties; spider silk is an attractive biopolymer known for its excellent strength and toughness [7][8][9] , and inspired by the water droplets on a spider's web, Jiang et al. [8] designed a series of functional fibers with unique wettability.In recent times, biomimetic synthesis has emerged as the prevailing strategy for creating bioinspired materials, including biomimetic teeth, [10,11] biomimetic bone, [12,13] biomimetic nacre, [14][15][16] biomimetic spider silk, [17,18] and so on.Increasingly, there is a wealth of compelling evidence indicating that biomimetic mineralization harbors immense potential for the advancement of advanced materials.
Biomineralization further contributes to organismal evolution through the deliberate design of organismmaterials integtators. [19]With the rapid development of materials science, the integration strategy of materials with living organisms has gradually entered into the researchers' field of vision and become one of the active and important research frontiers, which is conducive to promoting the functional evolution of living organisms. [20,21]Researchers have explored the use of functional materials to enhance organisms through biomimetic pathways, expanding the current understanding and application of biomineralization.For instance, red blood cells (RBCs), when reconstructed and loaded with diverse functional materials such as adriamycin (DOX), Fe 3 O 4 nanoparticles, and ATP biosensors, exhibit a spectrum of capabilities including oxygen delivery, drug transportation, magnetic manipulation, and toxin detection. [22]The utilization of these organism-material integtators greatly facilitates the controlled conveyance of engineered cells.Beyond the modification of an organism's inherent functions, the amalgamation of external materials with an organism possesses the potential to engender a novel entity, manifesting noninnate characteristics.As an illustration, the inclusion of materials onto algae could induce the production of hydrogen instead of oxygen during photosynthesis, while intracellularly implanted particles may serve as functional organelles.Biomineralization research has evolved from controlling material crystallization within organisms to utilizing materials for biological improvements, opening up new research and application possibilities.
In this review, we focus on biomineralization-inspired materials biomimetic synthesis strategies, and their applications in biomedicine.In the second part, we explore two aspects of the inspiration derived from biomineralization, including a novel approach to material synthesis-the inorganic polymerization strategies, and organismmaterial integrators.In the third part, we demonstrate the application of inorganic oligomers in hard tissue repair and discuss the important role played by the organismmaterial hybrids in the biomedical field in three parts: vaccine improvement, biomedical therapy, and artificial organelles.Finally, we summarize and discuss the current progress and challenges of biomineralization, and look forward to the expected future progress.

| INSPIRATION FROM THE BIOMINERALIZATION
To date, investigators have endeavored to emulate the biomineralization mechanism for the purpose of formulating an array of sophisticated biomimetic materials.In this section, first, we delineate a novel methodology that encompasses, the modulation of crystal synthesis precursors through the utilization of organic small molecules, and second, the construction of organism-material integrators.This approach serves to elucidate the fresh perspectives introduced by biomineralization in the domain of material synthesis.Such an approach indicates that the exploration of biomineralization has transcended the confines of diverse disciplines, encompassing materials science, polymer chemistry, and biology.

| Inorganic ionic polymerization and organic-inorganic copolymerization
Due to the optimal characteristics exhibited by biominerals, a profound comprehension of biomineralization holds paramount significance for the biomimetic formulation and synthesis of functional materials.Nucleation and crystallization represent pivotal physical phenomena in the genesis of geochemical, biological, and synthetic materials.Although the classical crystallization theory (CNT) has enjoyed widespread acceptance among researchers for the past century, an increasing body of theoretical calculations and experimental findings has revealed substantial deviations in the crystallization processes within diverse reaction systems during biomineralization from the classical "nucleation-growth" paradigm. [23,24]Nonclassical crystallization pathways (NCCPs) serve as a valuable framework for elucidating the intricate morphology and configuration of minerals engendered through biomineralization.They offer novel perspectives and methodologies to deepen our comprehension of the biomineralization process, consequently facilitating the synthesis of biomimetic mineralized materials.NCCPs propose the existence of various intermediate substable phases preceding the formation of thermodynamically stable phases.These phases encompass prenucleation clusters, [25] liquid precursors, [26] amorphous phases, [27] nanoparticles, [28] and other entities collectively referred to as nucleation precursors.In the realm of biomimetic mineralization research, emphasis is placed on the synthesis of stable nucleation precursors.The subsequent application of these precursors enables controlled synthesis in the realm of biomimetic materials.For instance, Gower et al. introduced charged polymers, such as poly(aspartic acid) [26,29,30] or poly(acrylic acid), [31,32] into a solution system containing calcium and carbonate ions.They leveraged the robust interactions between the carboxyl groups of the polymers and calcium ions to impede nucleation, resulting in the formation of relatively stable dense liquid precursors-well-recognized biomimetic mineralized precursors.Nevertheless, stabilizers with such strong interactions present a dual nature.While they effectively stabilize the cluster precursor, their tenacity hinders facile removal, leading to the exclusive formation of organic-inorganic complexes.This limitation restricts their application in materials synthesis.
Liu et al. presented a novel biomimetic mineralized precursor that combined biomineralization and polymer chemistry, termed inorganic ionic oligomers.The investigation substantiates the efficacy of small molecules in acquiring substable crystalline precursors, thereby offering a robust framework for controlling crystallization.This achievement establishes a solid foundation for the synthesis and application of biomimetic materials.

| Inorganic ionic polymerization
Conventional inorganic materials are usually formed by classical crystal nucleation, a process by which ions, atoms, or molecules of a solute nucleate from solution and form a stable nuclear seed, which then continues to grow in solution to form a complete crystal. [33]However, due to the limitation of classical crystallization, the materials obtained by conventional methods are usually powder particles rather than bulk wholes. [34]Since powder particles are not characterized by structural continuity and controllable shape at the macroscopic level, their applications are greatly limited.37][38][39] Polymeric materials are usually formed by organic monomers through covalent bond-based polymerization and cross-linking reactions, which have the advantages of plasticity and structural continuity, for example, plastics and rubbers.Compared with traditional inorganic materials, polymeric materials have higher reaction controllability and are widely used in human daily life. [40]In the process of polymer reaction monomer condensation, the addition of capping molecules can effectively prevent polymerization, thus stabilizing the polymer structure. [26]When the capping molecule is removed, the polymerization reaction can occur again.If the capping method commonly employed in polymer materials can be adapted for stabilizing nucleating precursors in bionic mineralization, it holds the potential to yield an entirely novel class of bionic mineralized materials.Inspired by this, Liu et al. [41] proposed an inorganic ionic compound capping strategy based on hydrogen bonding by drawing on the covalent capping strategy in polymer chemistry, and successfully prepared inorganic ionic oligomers similar to polymer monomers, which were used as precursors to realize the polymerization and crosslinking growth of inorganic compounds.
Liu et al. chose a common calcium carbonate (CaCO 3 ) in inorganic materials as a model, used ethanol with a low dielectric constant as a solvent, and triethylamine (TEA), a small alkaline organic amine molecule, as a capping agent, and successfully prepared a large number of calcium carbonate oligomers (CCOs) with controllable molecular weights (Figure 1A).The low dielectric constant properties of ethanol can enhance the hydrogen bonding force between TEA and calcium carbonate polyionic clusters, which in turn achieves the stabilizing effect on the clusters.By controlling the concentration of TEA, the regulation of the molecular weight of the oligomers between n = 3−11 was achieved (Figure 1C).Analysis using DAMMIF25, a program that enables the shape of a substrate to be determined from SAXS showed that the calcium carbonate oligomers were linear structures with a length of about 1.2 nm (Figure 1B), which were very similar to the monomers of macromolecules.Subsequently, the volatile nature of TEA was utilized to remove TEA and induce crosslinking of CCOs.The results of high-resolution TEM (HRTEM) can be observed that with the successive volatilization of TEA, the concentration of CCOs increases, and the shape changes from linear to branched, then to a network, and finally to a dense and continuous structure (Figure 1D).Since this process is similar to polymerization and cross-linking in polymer chemistry, it was named "Inorganic Ionic Cross-Linking."Through this cross-linking, moldable calcium carbonate with a continuous structure is synthesized instead of powdered calcium carbonate.
Furthermore, this approach can be extended to the restoration of single crystal materials.By harnessing the mobility and plasticity of inorganic ionic oligomers, it becomes possible to address imperfections on the surface or within the internal crevices and fissures of single crystals.These defects can be effectively filled, and their repair can be meticulously managed by controlling the crystallographic orientation of the single crystals.Notably, the crystal orientation within the restored area closely aligns with that of the substrate, resulting in a high degree of structural consistency.This process allows for the complete replication of the internal structure of the single-crystal material, suggesting that the inorganic ion cocrosslinking method has broad application prospects in areas such as hard tissue repair.

| Organic-inorganic copolymerization
In nature, the combination of inorganic minerals with biomolecules or biomacromolecules produces many ordered structures with unique properties and advantages.Many natural biomaterials have organic-inorganic composite structures that combine the flexibility of the organic phase with the strength advantages of the inorganic phase, [42] and therefore, organic-inorganic composites have received great attention.For instance, Zhou et al. [43] proposed a method to generate collagenyttrium oxide-stabilized amorphous zirconia hybrid scaffolds by introducing acetylacetonate-inhibited zirconia precursor nanodroplets into a poly(allylamine)coated collagen matrix.This polyelectrolyte coating triggered intracellular condensation of the precursor fibers into amorphous zirconia, which was subsequently converted to yttrium oxide-stabilized zirconia upon calcination.This strategy provided a method of using natural collagen templates to produce fused yttriastabilized zirconia (YSZ) with high mechanical strength, with potential applications as armor components or replacement parts for damaged hard tissues in the human body.However, combining the inorganic phase precisely and uniformly with the organic to form subnanometer composites remains a great challenge due to the completely different formation pathways of the inorganic and organic components.Inspired by ionic oligomers and their polymerization cross-linking F I G U R E 1 Synthesis of inorganic ionic oligomers.(A) Synthesis of (CaCO 3 ) n oligomers.(B) Radial distribution functions of (CaCO 3 ) n oligomers.(C) Mass spectra of (CaCO 3 ) n oligomers with different Ca:TEA molar ratios.(D) Stepwise chain growth of (CaCO 3 ) n oligomers observed by high-resolution transmission electron microscopy.Reproduced with permission. [41]Copyright 2019, Nature Publishing Group.TEA, triethylamine.
properties, Yu et al. [44] proposed a new reaction via organic-inorganic copolymerization by selecting inorganic calcium phosphate oligomer (CPO) as the inorganic ionic oligomer and acrylamide (AM) as the organic molecular monomer, and employing N,Nmethylbisacrylamide (MBAA), ammonium persulfate (APS), and tetramethylethylenediamine (TEMED), respectively, as the crosslinker, initiator and promoter (Figure 2A).Under the initiation of the initiator, free radical polymerization of AM monomers occurred through covalent bonding, while CPO produced ionic bonding polymerization during TEA removal.At the same time, calcium phosphate (CaP) and acrylamide monomers can be bonded together by hydrogen bonding, and finally polyacrylamide (PAM)-calcium phosphate copolymer (PCC) with a homogeneous internal structure is formed by copolymerization.Due to the complete continuity of the internal structure, the phase interface defects inherent in traditional composites are eliminated, and the fusion of organic and inorganic on the molecular scale is realized, which ultimately leads to optically transparent bulk materials.Similarly, Yu [45] and others tried to select sodium alginate (Alg)/polyvinyl alcohol (PVA) as the organic polymer and also use CPO as the inorganic ionic oligomer, which can also trigger the copolymerization of organic and inorganic units by drying treatment, and finally produce uniform organic-inorganic hybrid structure, that is, the inorganic ionic oligomers are uniformly distributed in the organic matrix (Figure 2B).These chemical interactions have inspired researchers to regulate the polymerization of inorganic ionic oligomers by applying external influences F I G U R E 2 (A) Illustration of the organic-inorganic copolymerization process.Reproduced with permission. [44]Copyright 2020, Wiley-VCH.(B) Illustration of the preparation process of PVA/Alg/HAP hybrid macrofiber and its network microstructure.Reproduced with permission. [45]Copyright 2019, Wiley-VCH.Alg, alginate; CaP, calcium phosphate; HAP, hydroxyapatite; PVA, polyvinyl alcohol.
on the organic matrix.These achievements suggest that inorganic ionic oligomers can readily participate in organic-inorganic interactions and can thus regulate the inorganic ionic polymerization of organic molecules in a manner similar to biomineralization processes.

| Materials integrated organisms
In conjunction with the inspiration drawn from biomineralization for the creation of novel crystalline precursors, endeavors have been undertaken to engineer organism-materials composites characterized by specific structures and functionalities.This emulation involves replicating the mediating role of organic matrices in inorganic minerals observed during biomineralization processes.The innate capacity of organisms to spontaneously generate hybridized materials is inherently constrained.Consequently, adhering to the fundamental tenets of biomineralization, investigations pertaining to surface modification of organisms or the introduction of organism-materials derived into living entities through chemical or chemical biology approaches have been elucidated.Presently, predominant methods for integrating organisms and materials encompass spontaneous integration, interfacial integration, and intraorganism integration.
Negatively charged biomolecules on the surface can combine with positively charged inorganic metal ions through electrostatic interactions, and when the whole system is in a supersaturated state, minerals are spontaneously formed on the surface of the organism, and thus can be directly used for organism-material integration.For example, viral surfaces are rich in negatively charged phosphorylated serine, glutamic acid or aspartic acid end-groups, which are favorable sites for mineral nucleation, and can be spontaneously mineralized by ion adsorption-deposition to assemble viralinorganic material integrals. [46,47]Nevertheless, the presence of active mineralization sites on the surface of organisms is inherently restricted.Consequently, researchers have endeavored to artificially introduce a mineralization-inducing layer onto the organism's surface to expedite the achievement of biomimetic mineralization.This process, recognized as interfacial integration, facilitates the seamless amalgamation of organism and materials.The most famous is the layer-by-layer (LBL) technology process, which is based on the alternate deposition of layers of material with opposite charges or intermolecular interactions to form a chemical coating with controlled thickness. [48,49]For example, in 2008, the LBL was first employed to boost the mineralization capabilities of yeast cells. [50]This method involved the sequential introduction of oppositely charged polyelectrolytes onto negatively charged cell surfaces, creating a mineralization-inducing layer rich in carboxylate groups.This layer served as nucleation sites for CaP mineralization, resulting in the formation of a CaP shell around the yeast cells, enhancing their storage time, protection, and delivery.In the process of organism-materials integration to achieve functionalization, beyond surface material introduction, an alternative approach involves the construction of "artificial organelles" within the cell.This internal modification can facilitate the organism's timely response to external stimuli, endowing it with novel functionalities. [51,52]or example, a study has synthesized biologically active CaCO 3 nanoparticles in situ in Saccharomyces cerevisiae cells, making the yeast cells a new type of nanomaterial reactor.The study was able to successfully prepare CaCO 3 nanoparticles in yeast cells by reacting a saturated solution of Ca(OH) 2 as a calcium source with CO 3 2− produced by respiration in living yeast cells.Its interaction with biomolecules (e.g., proteins, polysaccharides) was immobilized inside the cell, which can be used as an anticancer drug carrier. [53]However, while the intracellular delivery of organism-material integrators exerts a more profound influence on the organism and proves more efficacious than external material introduction, it confronts challenges such as a limited survival period, intricate synthesis pathways, and potential toxicity.These hurdles necessitate continued research and refinement by scientists.
In summary, the establishment of organism-material integrators using biomimetic mineralization technology represents a novel, straightforward, viable, and validated strategy.In contrast to the direct introduction of exogenous materials, the construction of organism-material integrators exhibits lower toxicity and enhanced biocompatibility.As further investigations unfold, this strategy is poised to assume a more prominent role in biomedical applications.

| BIOMEDICAL APPLICATIONS INSPIRED BY BIOMINERALIZATION
Inspired by biomineralization, scientists have designed and developed a wide range of biomimetic functional materials and applied them in various fields, among which the biomedical field is particularly prominent.Meanwhile, by emulating the biomimetic mineralization approach employed by living organisms, researchers have successfully introduced materials onto or within cells to engineer novel functional living entities, referred to as materials integrated organisms, which holds significant promise across a wide spectrum of research domains, as they not only ensure the normal physiological activities of organisms but also bestow upon them unique, specialized attributes.This section will elaborate on the applications inspired from biomineralization in hard tissue biomimetic repair, vaccine improvement, universal blood transfusion, tumor therapy, and arthritis treatment.

| Hard tissue biomimetic repair
Hard tissues are structures formed within living organisms through a process known as biomineralization, primarily utilizing protein molecules as templates.These tissues often serve vital functions, including protection, support, locomotion, and feeding.Examples of hard tissues in various organisms include vertebrate teeth and bones, mollusk shells, and echinoderm exoskeletons.Teeth and bone are a class of hydroxyapatite (HAP)organic composite tissues with a remarkably ordered crystal structure, exceptional mechanical strength, and are pivotal for activities like chewing and providing structural support.However, the human body's capacity for self-repair of teeth and bones is limited. [54]Bone is a vascularized mineralized connective tissue and as such has some ability to self-heal from microcracks and some types of minor fractures.However, as we age, the calcium and phosphorus content of human bones continues to decline, leading to osteoporosis and susceptibility to fragility fractures, and when the injury exceeds a critical size (usually set at 2 cm), the bone tissue fails to heal on its own, and in severe cases, can lead to disability. [55]eeth are the hardest and most wear-resistant part of human biomineralization, however, when acids from bacteria and food debris accelerate the accelerated dissociation of tooth minerals, resulting in an imbalance between mineralization and demineralization, dental caries can result.[58] The exploration of hard tissue repair mechanisms plays a pivotal role in facilitating the restoration of these tissues' physiological functions, thus improving human health and quality of life.
Among the biomineralization processes in the human body, the most typical one is the mineralization process using collagen as a template. [59]Teeth and bones are rich in type I collagen fibers, and an important process in tooth repair and bone repair is collagen mineralization, so the study of collagen mineralization has important clinical significance for hard tissue repair.Collagen molecules in the cell are precollagen peptides with longer chain lengths.Precollagen peptide molecules can form intrachain disulfide bonds between molecular sequences, allowing the collagen molecule to form a triple helix structure.They are then secreted into the extracellular matrix.They are subsequently cleaved by proteases and then polymerized by alignment to form protofibrils, which are neatly aligned into highly ordered bundles of collagen fibrils. [60]Collagen fibrils have a natural banded structure, which is due to the different distribution of charge density contained in the fibers in different regions. [61]Collagen mineralization can be divided into extrafibrillar and intrafibrillar mineralization, [62] where intrafibrillar mineralization of collagen is characterized by the presence of HAP within the collagen fibers and the arrangement of minerals in an overall oriented order.Since the mechanical properties of biological hard tissues are mainly determined by the degree of mineralization within the mineralized collagen fibers, studies related to collagen intrafibrillar mineralization have attracted more interest from researchers.For example, Shao et al. [63] used citric acid to modify collagen molecules through hydrogen bonding in bone tissues to reduce the interfacial energy between ACP and collagen fibrils, promote the penetration of ACP into collagen, and greatly increase the degree of mineralization of collagen fibrils.In this section, our emphasis will be directed towards the forefront applications of bionic repair for hard tissues employing inorganic ionic co-crosslinking methodologies.

| Tooth repair
Teeth represent the most highly mineralized hard tissues in vertebrates, composed of three distinct layers from outer to inner: enamel, dentin, and pulp. [64]Enamel, the outermost layer, is the most mineralized hard tissue in vertebrates, comprising 96% hydroxyapatite (HAP), 1% organic matter, and 3% water. [65]It possesses a complex hierarchical structure and performs crucial biological functions.Dental caries, a common affliction of dental hard tissues, arises from an imbalance between the demineralization and remineralization processes in teeth.Mature enamel, being acellular, has limited regenerative capabilities after damage, [54] making it a critical protective layer for teeth.Consequently, dental caries typically initiate in the enamel layer, underscoring the importance of enamel remineralization in addressing primary dental caries.Previous research endeavors have explored a variety of techniques for enamel restoration.These include methods like direct solution mineralization, [66,67] hydrogel-driven mineralization, [68][69][70] nanoparticle-based restoration, [71] protein/peptide-induced mineralization, [72][73][74] and precursor assembly. [64,75]Yet, it's imperative to emphasize that none of these approaches currently lends itself to clinical application.Yang et al. [76] established a universal biomineralization pathway for the repair of biological hard tissues by using biomacromolecule lysozyme nanofilm (PTL) as an adhesive substrate and mineralization template, and prepared hydroxyapatite material (HAP@PTL) with excellent mechanical properties and good bioactivity by mineralization in a "bottom-up" manner in in vitro bionics.Subsequently, Yang [77] mixed PTL with C-AMG, a synthetic protein that mimics the functional region of C-Ame, to form a coating (PTL/C-AMG), which successfully biomimicked enamelogenic proteins, remineralized carious teeth, and facilitated the generation of enamel-mimicking structures.
In addition to biomimetic proteins and molecules, scientists have discovered that replication of tooth enamel structures can be achieved by a nonclassical crystallization strategy.Increasing empirical support points to the occurrence of an integrated crystalline-amorphous interface in biomineralization processes at the growth frontier.Specifically, this process involves the encapsulation of the crystalline mineral phase by its amorphous precursor phase, thereby ensuring the uninterrupted progression of epitaxial construction.This phenomenon is notably exemplified in various instances, such as the crystal growth frontiers observed in zebrafish fin bone and nacre. [78,79]nspired by the application of inorganic ionic polymerization and cross-linking in single-crystal restorations, Shao et al. [80] harnessed calcium phosphate ion clusters (CPICs) for the restoration of damaged enamel surfaces.In this investigation, CPICs were utilized as precursor solutions and carefully applied to acid-etched enamel surfaces.Through an in situ cross-linking process, a continuous, densely structured amorphous calcium phosphate (ACP, Ca 3 (PO 4 ) 2 -nH 2 O) layer was fabricated, effectively simulating the biomineralization front.This process successfully induced the growth of a 2.7 μm remineralized enamel layer (Figure 3).Notably, the restored layer seamlessly integrated with the original enamel, exhibiting an amorphouscrystalline interface reminiscent of natural mineral growth.This approach achieved a continuous restoration of the enamel lattice while preserving the intricate multilayered enamel structure.Mechanically, the restored enamel layer demonstrated properties on par with natural enamel, with a Young's modulus of 87.26 ± 3.73 GPa, a hardness of 3.84 ± 0.20 GPa, and a coefficient of friction measuring 0.18 ± 0.008.This study employs inorganic ionic polymerization and cross-linking techniques to substantiate the potential for precise replication of intricate biological assemblies through artificial means.It underscores the capacity to integrate synthetic materials into biomimetic constructs.Notably, this research effectively addresses the medical challenge associated with nonrenewable enamel, thus advancing the paradigm of dental restoration from a conventional "filling" approach to a more progressive "bionic regeneration" strategy.Building upon the synthesis approach initially developed by Shao et al., Wang et al. [81] applied a modified version of this method to elucidate that the utilization of calcium phosphate nanoclusters (CaP NCs) as a precursor for the repair of eroded enamel yields an augmentation in the hardness of acid-etched enamel, effectively aligning it with the hardness of intact, healthy enamel.These findings underscore the substantial clinical potential of CaP NCs for managing early dental erosion, offering promising prospects for clinical applications in this context.
Dentin resides beneath the enamel layer, and the breach of enamel boundaries by dental caries leads to the formation of dentin caries.With the exposure of dentin, it becomes susceptible to infiltration by food remnants, bacteria, and metabolic byproducts, rendering effective cleansing challenging.Neglected in its early stages, superficial caries progresses to dentin demineralization.Consequently, the imperative lies in dentin restoration, with the pivotal focus being the remineralization of dentin collagen.In earlier investigations, Olszta et al. [82] achieved the internal mineralization of collagen fibers employing calcium carbonate based on polyacrylic acid (PAA).They introduced the hypothesis that polymerinduced liquid precursor (PILP) systems facilitate collagen mineralization.Subsequently, Saeki et al. [83] implemented a method involving the infiltration of PILP containing 100 μg/mL polyaspartate into demineralized dentin, simulating the effects of dental caries induced by various cariogenic bacteria.Remarkably, this approach successfully achieved dentin remineralization within a 14-day timeframe.Nonetheless, the mineralized restorations achieved via these techniques displayed a relatively limited longevity, typically within the range of 2 weeks to 2 months.This abbreviated period of effectiveness posed a notable constraint on the clinical feasibility of bionic mineralized dentin restorations.Subsequently, Chen et al. [84] discovered that the process of cross-linking dentin collagen with glutaraldehyde had the potential to facilitate biomimetic remineralization of dentin, consequently enhancing the mechanical characteristics and biostability of dentin tissue.This treatment led to a notable reduction in the remineralization duration, reducing it from 7 days to just 2 days.Nonetheless, it is crucial to acknowledge that while glutaraldehyde and similar substances do expedite collagen fiber mineralization to some extent, their inherent toxicity to living organisms necessitates the pursuit of alternative approaches for the swift and efficacious establishment of biomimetic organic-inorganic interfaces in the context of hard tissue regeneration.Yang et al. [85] covalently grafted a hydrophilic polyethylene glycol (PEG) molecule onto a lysozyme molecule (lyso-PEG), and obtained an emulsion system enriched with lyso-PEG amyloid oligomers by inhibiting the hydrophobic force between unfolded lysozyme.The experimental results showed that the coating could simply and quickly attach inside the dentin tubules, inducing dentin remineralization and deeply sealing the dentin tubules, realizing a gentle treatment of dentin sensitivity.
Drawing inspiration from the remarkable capacity of inorganic ionic oligomers to engage with organic molecules, Yan et al. [86] accomplished the development of an organic-inorganic biomimetic interface through the expedited cross-linking of calcium phosphate oligomers (CPOs) onto a collagen matrix.The monodisperse clusters of CPO gels, characterized by an average diameter of 1.2 ± 0.2 nm, exhibit the inherent ability to spontaneously cross-link through the volatilization of the solvent.When the CPOs was applied as a coating on a precast collagen membrane, it swiftly generated a continuous CaP layer on the collagen membrane within a mere 5 min (Figure 4A).This process established a dense and unbroken CaP-collagen hybrid.The technique was devised for the prompt in situ restoration of dentin, wherein the CPOs rapidly cross-linked on the dentin surface, forming a continuous, dense seal in just 5 min, with a filling depth exceeding 5 μm.The seal layer subsequently underwent crystallization within the salivary environment, ultimately reverting to a structure akin to natural dentin.In this context, the structurally integrated organic-inorganic interface matched that of natural dentin.The restored dentin displayed impressive mechanical properties, with a Young's modulus and hardness measuring 23.95 ± 3.65 and 0.58 ± 0.04 GPa, respectively.Moreover, animal experiments provided compelling evidence for the viability of this approach.Following the application of CPOs to acid-eroded rat teeth, the exposed dentin pores were effectively sealed, delivering significantly superior outcomes compared to existing clinical products.Likewise, Kim et al. [89] conducted a preliminary 1-min pretreatment of etched dentin collagen fibers with CPICs or metastable CaP.This preliminary treatment led to a biomimetic remineralization process and yielded a notable enhancement in .Reproduced with permission. [80]Copyright 2019, American Association for the Advancement of Science.SEM, scanning electron microscope.microtensile bond strength.These investigations underscore the potential of inorganic ionic cross-linking as a compelling approach for the expeditious and efficient restoration of rigid biological tissues.This, in turn, underscores the broader applicability of inorganic ionic oligomers within the domain of biomedical materials (Table 1).

| Bone repair
Bone constitutes a fundamental element in human health and daily functioning, primarily serving as a scaffold for structural support, protective encasement, mineral reservoir, and hematopoietic site.While the human body possesses intrinsic regenerative capabilities, bone defects arising from various pathological conditions, such as trauma, tumors, inflammation, or osteoporosis, often exceed the innate healing capacity.As a result, effective clinical techniques are indispensable to stimulate bone regeneration.Presently, key research areas in bone repair encompass osteoporosis, characterized by an imbalance between bone formation and resorption, and bone defects arising from traumatic injury, neoplastic growth, or infection.Without intervention, bone defects remain unhealed, leading to chronic pain, impaired mobility, psychological distress, and sleep disturbances.This detrimentally affects the patient's F I G U R E 4 (A) Schematic illustration of dentin remineralization.Reproduced with permission. [86]Copyright 2022, Wiley-VCH.(B) Schematic illustration of the BOH fabrication.Reproduced with permission. [87]Copyright 2022, American Chemical Society.(C) Schematic illustration of the organic-inorganic biofibers fabrication for bone fracture healing.Reproduced with permission. [88]Copyright 2022, Elsevier Ltd.Alg, alginate; BOH, bone-like hydrogel; CaP, calcium phosphate; CPO, calcium phosphate oligomer; HAP, hydroxyapatite; PECM, periosteal-decellularized extracellular matrix; PVA, polyvinyl alcohol.quality of life and necessitates bone repair procedures to restore bone integrity and functionality. [90]Conventional bone repair materials are typically constructed in vitro and then transplanted into the body for osseointegration.The process of bone formation, on the other hand, is the mineralization of the collagen matrix using mineralization precursors.Shen et al. [91] extracted RNA from mouse bone marrow mesenchymal stem cells (mBMSCs) and reacted it with supersaturated CaP solution to form RNA-stabilized amorphous calcium phosphate (RNA-ACP) nanorobots, which can be used for collagen mineralization.Meanwhile, by adding ribonuclease (RNase) to inhibit the formation of unwanted bone in tissues other than bone and teeth, rapid and controlled collagen mineralization was achieved, and bone healing was successfully promoted.Yao et al. [92,93] embarked on the development of CaP NCs with a diminutive 1 nm size.They achieved this feat by emulating the intricate bone formation process and judiciously providing the essential mineralized precursors required for assembly to living organisms.This innovation involved the synergistic incorporation of poly(acrylic acid) and poly(aspartic acid) to create macroscopic bulk CaP polymer liquid precursor nanomaterials.This resultant material exhibited characteristics of being mineral-rich, viscous, and displaying excellent fluidity.Notably, it demonstrated the ability to infiltrate osteoporotic bone for tissue repair, as evidenced in in vitro experiments.The repaired bone tissue exhibited a smooth surface devoid of obvious defects, closely resembling normal bone.This groundbreaking achievement not only transcended the traditional approach of merely delaying osteoporosis progression but also realized the actual reversal of this condition.Subsequently, Yao et al. extended the application of this material to the repair of cranial defects in animal models, yielding similarly promising outcomes.By utilizing the CaP NC approach for repair, a significant breakthrough was achieved in the clinical treatment of osteoporosis.This innovative method went beyond the traditional approach of primarily delaying the progression of osteoporosis, and successfully realized the reversal of this debilitating condition.
Critical-sized bone defects, which elude spontaneous healing, present a formidable challenge within the realm of clinical treatment.To tackle this issue, Zhao et al. [87] employed a pioneering approach by orchestrating the creation of an osteogenic microenvironment through the amalgamation of a biomimetic hydrogel and nanohydroxyapatite (nano-HAP).Drawing inspiration from the realm of organic-inorganic co-crosslinking, Zhao et al. judiciously harnessed crosslinked periostealdecellularized extracellular matrix (PECM) as an organic scaffold and leveraged the potential of CPOs to establish robust organic-inorganic interactions (Figure 4B).This strategic move ensured the in situ mineralization of bone-like nano-HAP within the hydrogel matrix.The resultant biomimetic bone-like hydrogel (BOH) was found to be adept at fostering bone mineralization, orchestrating the construction of an immunomodulatory microenvironment, and enhancing in vitro angiogenesis.Notably, animal studies corroborated that BOH expedited the regeneration of cranial bone defects in rats, effecting substantial regeneration and remodeling of extensive bone defects within an 8-week time frame, surpassing the performance of numerous previously reported hydrogel systems.This investigation deepens our comprehension of biomaterial design for hard tissue repair, accentuating the advantages of inorganic ionic oligomers in facilitating the construction of organic-inorganic interactions, thereby providing an alternative avenue for the development of advanced biomimetic materials.Furthermore, the issue of nonunion bone fractures represents a substantial and escalating challenge within the field of orthopedics.There is a discernible upward trajectory in the incidence of fracture cases each year, concomitant with a rise in the prevalence of patients manifesting nonunion or experiencing delayed healing subsequent to fractures.While clinical materials have played a role in facilitating fracture healing, such as metallic constructs and composite materials, they fall short of meeting the requisite standards.This deficiency stems from their comparatively sluggish degradation rates, constrained osteogenic efficacy, inadequate osseointegration potential, and suboptimal mechanical characteristics.To address this issue, Yao et al. [88] have successfully addressed this challenge by developing a biocompatible and biodegradable organic-inorganic polyvinyl alcohol-arginine-calcium phosphate (PVA/ Arg/CaP) biofiber (Figure 4C).This was achieved through an inorganic ionic polymerization method utilizing CPOs.The biofiber, which has a hybrid composition, encompasses CaP nanoclusters as the inorganic building blocks, with PVA serving as the organic polymer matrix due to commendable biocompatibility and biodegradability.The inclusion of arginine, an amino acid replete with carboxyl and amino groups, plays a pivotal role as a molecular bridge, facilitating robust interactions with both CaP and PVA, thereby stabilizing the CaP nanoclusters.The results of animal experiments substantiated the efficacy of the prepared biofibers.They could be affixed to mouse tibia fracture sites, and over time, these biofibers degraded, liberating ultra-small CaP nanoclusters.Subsequently, these nanoclusters infiltrated the fracture site and underwent crystalline transformation within the newly formed collagen matrix, ultimately healing the tibia fracture.The regenerated bone displayed mechanical properties and mineral density akin to those of normal bone, underscoring the biofiber's robust bone-regeneration capabilities.
These studies are emblematic of a scientific paradigm that leverages insights from biomineralization processes to develop biomimetic mineralization techniques.By incorporating inorganic ion polymerization cross-linking methods, these materials are then applied to biomineralization systems for biomedical applications, heralding significant breakthroughs in the field.

| Vaccine improvement
Materials can be optimized for vaccines by modulating interfaces and building microenvironments.Vaccination stands as the most efficacious medical intervention in combating viral infectious diseases that pose a substantial threat to public health on an annual basis. [94]evertheless, the heat sensitivity of live attenuated vaccines presents a significant challenge.Elevated temperatures can lead to the virus's dissociation, swelling, inactivation, and loss of immunogenicity.Consequently, these vaccines cannot be stored at ambient temperatures and necessitate refrigeration to maintain their quality. [95]Additionally, the cold chain method for vaccine preservation proves to be prohibitively expensive for many developing countries with limited resources.Therefore, the imperative arises to develop heat-resistant vaccines that can be stored at room temperature without a substantial decline in immunogenicity.Inspired by the mineralized state of viruses, the rational design of viral biomimetic materials can be used to make heat-resistant vaccines and improve the storage of vaccines.Wang et al. [96] applied in situ biomineralization of CaP mineral shells to JEV viruses to enhance the thermal stability of SA14-14-2 vaccine.Due to the negative charge on the surface of JEV virus particles, Ca 2+ can spontaneously accumulate around these virus particles and act as nucleation sites for in situ CaP mineralization.The experimental results show that the vaccine acquires an eggshell-like coating composed of CaP, thus becoming robust with excellent thermal stability.Notably, the nucleoshell structure of this vaccine-biomaterial mixture is biodegradable and allows for the adjustment of the shell thickness while preserving the original efficacy of the vaccine.Similarly, inspired by the fact that heat-stable organisms in nature, such as hot spring bacteria and tropical plants, enhance their heat resistance by enriching amorphous silica through biosilicification, Wang et al. [97] introduced a silica layer on the surface of human enterovirus 71 (EV71), which significantly improved the thermal stability of the vaccine.Mechanistic studies showed that silica nanoclusters on the surface of the virus formed hydrogen bonds with nearby water molecules, thereby protecting the vaccine from destructive factors such as molecular mobility, pH and ionic strength changes.When this biomimetic silica approach was applied to a clinically approved polio vaccine, the vaccine retained 90% potency after 35 days of storage at room temperature.This innovative approach significantly simplifies the storage requirements of vaccines and offers a promising solution for improving vaccine stability.
For some vaccines, pre-existing antibodies sometimes play an opposite role in the vaccination process, leading to the phenomenon of fatal antibody-dependent enhancement (ADE) infections.Therefore, to avoid recognition between the virus and pre-existing antibodies, some strategies are needed to promote vaccine stealth.For example, Wang et al. [98] developed a generalized surface camouflage strategy using in situ mineralization to obtain CaP shells as an example of dengue virus (DENV), which can evade the recognition of pre-existing antibodies, thus effectively eliminating the ADE for in vitro and in vivo infections (Figure 5A).Meanwhile, due to the pH-responsive nature of CaP, the mineralized vaccine can be spontaneously degraded under low-PH conditions, releasing the encapsulated virus particles to maintain the immunogenicity of the virus.In addition, previous studies and clinical data have F I G U R E 5 (A) Scheme of the formation of calcium phosphate nanoshells on viral surfaces.Reproduced with permission. [98]Copyright 2017 Royal Society of Chemistry.(B) Schematic description of vaccine engineering with a dual-functional mineral shell.Reproduced with permission. [99]Copyright 2016, Wiley-VCH.
shown that anti-Ad5 immunization can neutralize the virus before it enters the target cells, thus inhibiting the effectiveness of the vaccine. [100,101]To improve the effectiveness of the Ad5 vaccine, Wang et al. [99] applied the CaP shell strategy to the Ad5 vaccine to generate CaP-Ad5 heterodimers with a core-shell structure, which effectively protects the encapsulated virus from neutralization and removal of pre-existing immunity, and successfully improves the vaccine's effectiveness (Figure 5B).The above work solved the problems of insufficient shielding effect and low in vivo efficiency of current vaccination by introducing CaP shell.Meanwhile, the CaP shell also has good biocompatibility, nontoxicity and biodegradability, which provides a feasible strategy for the development of efficient vaccines.
In addition to using nano-scale mineralized shells for vaccine modification, micro-scale materials have also been used to modify and develop viral vaccines.Typically, wholevirus vaccine strategies (e.g., attenuated or inactivated) can be used to directly convert potent viruses into vaccines.However, the reduced immunity, safety concerns, and time-consuming manufacturing process of whole-virus vaccines have hindered their widespread use. [102,103]urrently, the emergence of many new viral outbreaks leading to epidemic diseases has prompted a growing demand for the development of safe and easily accessible vaccines. [104]Hydrogel is a versatile and flexible material with excellent biocompatibility and remarkable permeability to oxygen and nutrients.Recent studies have shown that strong strains can be converted into vaccines by constructing microenvironments for encapsulated viruses using hydrogels.Hao et al. [105] developed a virus-encapsulated hydrogel called Vax, which consists of chitosan oligomer hydrogel with built-in adjuvants as a virus capture agent and calcium carbonate nanoparticles (nano-CaCO 3 ) as a stabilizing agent and a source of Ca 2+ .Chitosan scaffolds with positively charged side chains efficiently capture viruses through electrostatic interactions, while their self-adjuvant properties activate innate immune responses and cell aggregation through the activation of pattern recognition receptors (PRRs).Thus, the hydrogels generated an inflammatory ecological niche for viral uptake and antigen processing, successfully promoting antigen presentation in lymph nodes (Figure 6), leading to effective humoral and cellular immunity.Experimental results show that a subcutaneous vaccine consisting of live Zika virus electrostatically encapsulated in a self-adjuvant hydrogel enables mice to elicit effective immunity and protects them from lethal infections.In contrast to prevailing vaccine engineering approaches, like live attenuated and inactivated vaccines, which still entail safety concerns and F I G U R E 6 Schematic of the virus-entrapping hydrogel (Vax).Schematic showing that Vax is prepared by the presence of nano-CaCO 3 and viruses.The administration of Vax forms a niche, where PRRs are activated to facilitate immune cell recruitment and the activation of innate immune responses, leading to antigen presentation, the elevation of GC B cells and cross-presentation in lymph nodes.Thus, Vax induces robust antigen-specific responses and memory responses.Reproduced with permission. [105]Copyright 2023, Wiley-VCH.GC, germinal centre; PRRs, pattern recognition receptors.
protracted development cycles, this strategy holds great promise in the prevention of emerging infectious diseases.It does so by obviating the necessity for intricate viral bioengineering in vaccine development.The notion of leveraging materials to transform viruses into vaccines introduces a fresh perspective on addressing the challenge of emerging viruses for which no vaccines currently exist.

| Biomedical therapy
The materials can modulate the outside surface of the cell of an organism to achieve a variety of therapeutic treatments.To date, the organism-material hybrids has found many potential applications in biomedical therapies such as strategies in tumor treatment, blood transfusion and so on.In this section, we present some representative work.

| Tumor treatment by biomineralization
Tumors have been one of the deadliest diseases and are on the rise year after year. [106]Traditional tumor treatments, including surgical resection, chemotherapy, and radiotherapy, have certain problems, including toxic side effects, treatment tolerance and resistance, invasive surgery, limited efficacy, and poor targeting.These problems make tumor treatment complex and challenging.Therefore, researchers are constantly seeking new therapeutic strategies to improve the efficacy of treatment and reduce adverse effects.
Cellular pathological calcification (CPC) is an abnormal biomineralization phenomenon that refers to the deposition of excessive calcium salts in or around cells, which can lead to damage in a variety of cell types, which may become a new strategy for tumor therapy.Based on the upregulation of folate receptor (FR) in cancer cells, Zhao et al. [107] proposed a drug-free cancer treatment of cancer-celltargeting calcification (CCTC) as a safer alternative to tumor therapy.Cancer cells that selectively adsorbed folic acid (FA) molecules induced calcification and death due to the carboxylic acid moiety of FA that can specifically bind to Ca 2+ in biological fluids, thereby promoting calcium mineral nucleation.In this study, human embryonic kidney (HEK293) and cervical cancer (HeLa) cell lines were selected as FR-deficient and FR-enriched models, respectively.Experiments showed that when cultured in medium containing high levels of folate and Ca 2+ , the FR-deficient HEK293 cells maintained a smooth surface, whereas the surface of the FR-enriched HeLa cells exhibited significant calcification (Figure 7A), and the selective calcification of HeLa cells resulted in a severe decrease in cell viability (Figure 7B).Animal experiments demonstrated that CCTC treatment effectively inhibited tumor formation compared with the control and DOX treatment groups.Compared with conventional chemotherapy, CCTC treatment can effectively inhibit tumor growth and limit its metastasis without damaging normal cells, thereby substantially increasing the survival rate of the treatment (90%).Subsequently, Tang et al. [108] optimized the tumor calcification procedure and designed a novel polysaccharide concatenation (polySia) containing FA (tumor-targeting portion) and anionic polysialic acid, which can promote tumor calcification at physiological calcium concentration and achieve self-calcification of tumor cells.Results from animal experiments showed that after systemic administration of folate-polySia, the drug was mainly concentrated at the tumor site and inhibited the growth of cervical and mammary tumors and significantly increased the survival rate of mice.This calcium-mediated strategy for tumor suppression further demonstrates its great potential in clinical cancer therapy.In addition, calcium peroxide nanoparticles (CaO 2 NPs) modified on the basis of pHsensitive sodium hyaluronate have been shown to be used to generate artificial calcium overload stress, leading to cancer cell death. [109]In an acidic tumor microenvironment, CaO 2 NPs can slowly decompose into free Ca 2+ and H 2 O 2 , thereby altering calcium channels, impeding accurate calcium signaling and inducing cell death.Meanwhile, tumors are prone to calcification during Ca 2+ enrichment, which facilitates in vivo tumor suppression and CT imaging to monitor treatment effects.In contrast, normal cells have sufficient catalase to allow exogenous Ca 2+ to be pumped or stored through calcium channels and are therefore unaffected.

| Universal blood transfusion
The organism-material hybrids can also offer innovative solutions for blood transfusion applications.Blood transfusions are commonly employed in surgical procedures globally, however, the challenge of blood group compatibility, especially when dealing with rare blood groups, remains a persistent issue.Depending on the alloantigen, human blood groups consist of more than 20 blood group systems, of which the ABO blood group and the rhesus (Rh) blood group are the most closely related systems.When the D blood group substance (antigen) is present on an individual's red blood cells, it is known as Rh-positive blood and is indicated by Rh(+).Conversely, when the D antigen is not present, it is categorized as Rh-negative blood, denoted as Rh(−).Rh-negative blood, commonly known as "panda blood," is a rare blood type, so converting RhD-positive blood to RhD-negative blood has great clinical value.Previous studies have successfully utilized enzymatic hydrolysis to remove A or B antigen on the surface of red blood cells to convert red blood cells to universal O blood type. [110]However, immunogenic Rh epitopes are closely associated with the erythrocyte membrane, and the removal of Rh antigen-related peptides leads to erythrocyte membrane collapse and loss of biological function.
Based on this, Zhao et al. [111] developed a biocompatible anchoring molecule that immobilizes horseradish perhydrogenase (HRP) on the cell surface, catalyzes the decomposition of hydrogen peroxide, and promotes the cross-linking of poly(salivary acid) (PSA) and tyramine to form a gel network, which constructs a flexible gel shell (PSA-tyramine) on the surface of the erythrocyte (Figure 8) and effectively hides the rhesus D (RHD) antigen.This flexible gel shell ensured the stability and fluidity of the cell membrane.The encapsulated erythrocytes showed no immune response to Rh antigen, retained the same oxygen dissociation curve (ODC) as natural erythrocytes, and were preserved in serum for 8 days.In vivo examination demonstrated complete invisibility and indistinguishability from natural RBCs.Copyright 2016, Wiley-VCH.CCTC, cancer-cell-targeting calcification; FA, folic acid.
Materials can enter the cell at the subcellular organelle scale for long-term functional regulation of the organism.In the method of transforming organisms through the integration of materials, in addition to the transformation of the surface of the organism, it is also possible to construct a special "artificial organelle", which helps to regulate the ionic homeostasis of the cell and play the role of transmitting signals to help the organism respond to external stimuli in a timely manner, and give the organism a new function.Compared with the external integration of materials, the modification within the organism has a greater impact on the organism and the effect is more obvious, but it also faces challenges such as short survival period, complex synthesis route and potential toxicity, which need further research and improvement.

| Au-ODN for detoxication
Intracellular targeting strategies of artificial organelles can enable targeted delivery and reduce side effects in biomedical treatments.A number of specific organelles have been investigated for enhanced anticancer efficiency. [112,113]For example, triphenylphosphine (TPP)conjugated trialkoxysilanes can specifically target and disrupt the mitochondria of cancer cells.TPP can target the mitochondria of cancer cells while trialkoxysilanes induce silylation.This approach depolarizes and disrupts mitochondrial membranes, leasing the dysfunction of mitochondria and activating apoptotic pathways, and ultimately resulting in tumor inhibition in vitro and in vivo.Meanwhile, chemotherapy is an effective treatment for cancer therapy. [114]Drug therapies, such as adriamycin (DOX), inhibit DNA replication and induce apoptosis, but the drawback is its indiscriminate treatment of normal and cancerous cells with great side effects.It is well known that GC-rich oligodeoxynucleotides (ODN) can eliminate DOX from normal cells due to its high affinity for DNA. [115]owever, the utilization of ODN in vivo is limited by rapid degradation by nuclease, so it is necessary to develop a strategy that can resist ODN degradation.Based on this, Zhao et al. [113] designed a nonspecific gold oligonucleotide (Au-ODN) nanomaterial artificial organelle (Figure 9A).When this material is implanted in vivo, the oligonucleotide Reproduced with permission. [111]Copyright 2020, American Association for the Advancement of Science.
F I G U R E 9 (A) Preparation of Au-ODN nanocomposite and its working mechanism as an artificial organelle.(B) Normalized tumor growth curves in the control, DOX, Au-ODN+DOX and Au-ODN+DOX+NIR treatment groups (volume vs. time).Reproduced with permission. [113]Copyright 2018, Wiley-VCH.
F I G U R E 10 (A) Schematic diagram of membrane-coated nanothylakoid units (CM-NTUs).(B) Safranin-O staining of joint sections at 8 and 12 weeks in vivo effect of CM-NTU treatment on osteoarthritis was investigated in 12-week-old male mice.(C) Schematic illustration of establishment of the mouse model of osteoarthritis and the experimental design to evaluate the protective effects of CM-NTUs.DHE, dihydroethidium.Reproduced with permission. [118]Copyright 2022, Nature Publishing Group.
fragments can be well adsorbed on the gold nanocage, effectively binding the chemotherapeutic drug adriamycin, acting as a "scavenger" of DOX in the normal cells and avoiding cytotoxicity (Figure 9B).In vivo experiments showed that the nanocomposites exhibited selective effects in vivo, and the intracellularly implanted Au-ODN mainly accumulated in the liver.This approach establishes an effective defense against the harmful effects of DOX and demonstrates the potential of artificial organelles to improve the accuracy and safety of cancer therapy.

| CM-NTUs for osteoarthritis repair
Osteoarthritis is a prevalent age-related degenerative disease that often leads to disability and reduced quality of life in older adults.The progression of this disease is characterized by degeneration of articular cartilage and disruption of the metabolic homeostasis of chondrocytes, leading to pathologic chondrocyte ATP and NADPH depletion [116] as well as an increase in the production of reactive oxygen species (ROS) and matrix metalloproteinases (MMP). [117]An innovative approach to addressing osteoarthritis involves the creation of artificial organelles to support the metabolic demands of chondrocytes.
Inspired by plant photosynthesis, Chen et al. [118] devised a solution to restore ATP and NADPH levels within damaged chondrocytes by developing a nanoscale photosynthesis system.The system is based on plant-derived nanotubular vesicle units (NTUs) that can be independently controlled (Figure 10).To enable its use in humans, it is covered by a specific mature cell membrane, the chondrocyte membrane (CM).These CM-NTUs enter the chondrocyte efficiently through membrane fusion, avoiding lysosomal degradation.Once inside the cell, CM-NTUs photosynthesize in the presence of light, thereby increasing intracellular ATP and NADPH levels.This, in turn, enhances anabolic processes in degenerating chondrocytes.This artificial photosynthesis systematically addresses the energy imbalance and restores cellular metabolism, ultimately improving cartilage homeostasis and halting the pathological progression of osteoarthritis.By accomplishing "photosynthesis" in animal cells through a novel strategy, a new strategy based on the natural photosynthesis system for the treatment of degenerative diseases has been proposed.By rebalancing energy metabolism in animal cells, this system can rejuvenate senescent cells and effectively enhance cellular anabolism by providing essential energy and metabolic carriers (Table 2).

| CONCLUSION AND PROSPECTS
This review proceeds from biomineralization-inspired strategies for biomimetic synthesis of materials and their applications in the biomedical field.On the one hand, inorganic ionic polymerization and organic-inorganic copolymerization strategies play an important role in materials fabrication and have been exploited for their restorative functions in hard tissues (enamel, dentin, bone, etc.).On the other hand, the integration of biomimetic inorganic materials with organisms has been widely explored, including vaccine improvement, cancer therapy, blood transportation, arthritis treatment, and so on, providing new directions for the development of the fields of materials science, chemical biology, bioinorganic chemistry, and medicine.By learning from nature, the research field of biomineralization has achieved an expansion from the regulation of material crystallization by biological systems to the use of materials to improve the performance of living organisms, and then applied to the biomedical field, and has already made rapid progress, providing a new direction for the sustainable development of biology and materials.This field has also further blurred the boundaries between biological and nonbiological, providing new possibilities for the future development of biological and material science, and it is believed that the applications of biomimetic materials will become more widespread in the near future.Through continuous research and innovation in this field, we will better understand the interactions between biology and materials, promote further T A B L E 2 Examples of the strategy of organism-material hybrids.

Strategy
Location Dimension Application Ref.

F I G U R E 3
Repair of whole tooth enamel and its mechanical and microtribological properties.(A) High-magnification SEM image of the acid-etched enamel and repaired enamel.(B), (C) Confocal laser scanning microscopy (CLSM) images of cross sections of the whole tooth.The repaired layer was labeled with calcein, which emitted green fluorescence.(D), (E) Characterization of elastic modulus, hardness, and coefficient of friction of different enamel samples (native, etched, repaired)

F
I G U R E 7 (A) Schematic of CCTC.(B) Micrograph of selective calcification.(C) Cell viability after selective calcification.Reproduced with permission.

F
I G U R E 8 (A) Schematic of red blood cell (RBC) surface engineering and the blood transfusions of the obtained cell-material hybrids.(B) Survival profiles of RBCs after blood transfusion in vivo.(C, D) Analysis and comparison of the oxygen dissociation curves (ODC), Hill plot, and contents of 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) of native (black) and engineered RBCs (red).
in the fields of biomedicine and materials science, and open up new possibilities for future medical treatments and disease therapies.Despite the great achievements in biomineralization, challenges still remain.(1) The detailed formation mechanisms are not yet clearly known.(2) The practical application of inorganic ionic oligomers in tissues for repair is yet to be developed.(3) Precise regulation of the size, morphology, and physicochemical properties of the biominerals has not yet been achieved.(4) The biocompatibility of materials has become a major obstacle to the development of hybrid engineering.In any case, the exploration of biomineralization and the development of materials inspired by it will continue to be a pivotal avenue for advancing our comprehension of nature and the craft of materials science.
T A B L E 1