Biomimetic mineralization: construction and biomedical applications of biohybrid materials

Abstract

Biomineralization has a significant impact on natural evolution and can integrate inorganic minerals into living organisms. This is not only a biological strategy evolved during natural evolution but also a strategy prepared for the use of advanced biomaterials. Through biomimetic mineralized methods, researchers have developed multi-level ordered composites, which have excellent chemical and physical properties, controllable structures, and good biocompatibility. This article mainly introduces the principles of using biomimetic mineralization technology to prepare biohybrid materials in recent years, such as spontaneous mineralization, layer by layer self-assembly mineralization, “bridging” hybridization mineralization, regulating intracellular ion concentration mineralization, and genetic engineering. Then, we summarize the progress in biomedical applications such as active component protection, tumor treatment, hard tissue repair, and biological imaging. This provides a deeper understanding of the formation mechanism of nano-multilayer structures in biohybrid materials and the biological effects achieved by biomimetic mineralization. It also predicts future development prospects and problems for biohybrid materials.

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Tiantian Chen

Tiantian Chen received her MS degree from the School of Chemistry and Materials Science, Nanjing Normal University (China) in 2023. Currently, she is conducting her doctorate project on the design and construction of biomedical micro/nanomotors and their applications for cancer treatment, under the supervision of Prof. C. Mao and Dr M. Wan.

Yingjie Wang

Yingjie Wang was enrolled as a bachelor's student majoring in the School of Chemistry and Materials Science at Nanjing Normal University (China) in the September of 2022, under the supervision of Prof. C. Mao and Dr M. Wan. He is currently carrying out research work on biomedical functional materials.

Keheng Wang

Keheng Wang, studying materials science and engineering at the School of Chemistry and Materials Science, Nanjing Normal University (China), is currently a student in the research group of Prof. C. Mao and Dr M. Wan. His current research interests mainly focus on the treatment of liver cell damage and nanocomposite materials for drug delivery.

Min Dai

Min Dai was born in 2004, and graduated from Anfu Middle School, Ji'an City, Jiangxi Province (China). She is now an undergraduate majoring in Materials Science and Engineering, at the School of Chemistry and Materials Science, Nanjing Normal University (China). At present, she is studying in Prof. C. Mao and Dr M. Wan 's group.

Chun Mao

Chun Mao obtained his PhD in the Department of Polymer at Nanjing University (China) in 2004. Currently he is a professor at the National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science at Nanjing Normal University (China). His research interests include biomedical functional materials, micro/nanoscience and technology, and the diagnosis and treatment of diseases.

Mimi Wan

Mimi Wan obtained her PhD in the Department of Chemistry at Nanjing University (China) in 2015. Currently she is a researcher at Jiangsu Key Laboratory of Biofunctional Materials at Nanjing Normal University (China). In recent years, she has been engaged in the construction of biomedical functional materials (including mesoporous materials and micro/nanomotors) and their application in the treatment of blood-related diseases.

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1. Introduction

After a long period of natural evolution, many organisms have developed the ability to spontaneously form mixed structures of biominerals to adapt to harsh living environments. This phenomenon is known as biomineralization.¹ As a widely existing natural phenomenon, it is a biological process that precisely regulates the formation of inorganic materials, including crystal nucleation, growth, polymorphism, and orientation evolution.^2–5 Under the regulatory action of organisms, inorganic minerals produced by organisms usually have excellent physicochemical properties, which can strengthen the organism itself, and improve its survival ability and function.^6–8 For example, bird eggs produce a mineralized shell to protect embryonic development as a biological barrier.⁹ Sea urchins, diatoms and other marine organisms use biological mineral shells to defend themselves against invasion by natural enemies and external environmental pressure. Skeletons, coral skeletons and sponge needles provide mechanical support for organisms.^10–13 These cases all mean that in the process of natural evolution, organisms can obtain precise regulation of mineral synthesis based on their characteristics and needs, that is, by cleverly assembling inorganic minerals within organisms to achieve superior performance.^14,15 Inspired by the natural biomineralization process mentioned above, researchers have proposed a biomimetic mineralization strategy, developed and produced many hybrid organisms based on biomimetic mineralization technology.^16–19 By imitating and designing the structure of biominerals in nature, a multi-level ordered composite material with a controllable structure, excellent physical and chemical properties, and good biocompatibility is obtained, achieving structural or functional biomimetics (Fig. 1). Biomimetic mineralization is currently developing into a new research direction in the field of biomedical engineering. More and more research teams from various fields such as chemistry, physics, materials science, biology, and even biomedicine are devoting themselves to synthesizing and preparing biological nanomaterials with specific structures and functions through biomimetic mineralization strategies, forming biohybrid materials to achieve the goal of transforming living organisms.^7,20,21 This review summarizes the recent achievements in the understanding of biomedical engineering based on biomineralization, and the application of biomimetic mineralization technology in preparation of biohybrid materials. This includes the principles and methods of constructing biohybrid materials based on biomimetic mineralization mechanisms, and the main applications of biohybrid materials in biomedical fields (Table 1). The current state of the field of biomimetic inorganic nanomaterials for modifying living organisms is analyzed and summarized, and future opportunities and challenges in the field are outlined.

Fig. 1 Construction of biomineralized biohybrid materials and their biomedical applications.

Table 1 List of organisms that are employed for nanomodification by biomineralization

Biohybrid	Organism	Mineral material	Method	Application	Ref.
Abbreviations: nano mineralized cancer cells (NMCCs), bovine serum albumin (BSA), layer-by-layer (LbL), mesoporous silicon dioxide nanoparticles (MSNs), tobacco mosaic virus (TMV), encapsulin-produced magnetic iron oxide nanocomposites (eMIONs), cerium oxide nanoparticles (CONPs), hydroxide hydroxyapatite (HAP), red blood cells (RBCs), outer membrane vesicles (OMVs), glucose oxidase (GOx), Prussian blue (PB), extracellular matrix (ECM), dental pulp stem cells (DPSCs), biomineralization inducing nanoparticle (BINP), ovalbumin antigen (OVA), human influenza A virus (IAV), manganese phosphate (MnP), silk fibroin (SF), phycocyanin (PC), adenovirus serotype 5 (Ad5), japanese encephalitis vaccine virus (JEV), saccharomyces cerevisiae (SaC), human yellow fever vaccine 17D (YF-17D), neural stem cells (NSCs), hyperbranched polyglycerols (HPG), polypyrrole (PPy), cowpea chlorotic mottle virus (CCMV), calcium phosphate (CaP), human serum albumin (HSA), amorphous calcium phosphate (ACP), strontium titanate (STO), bismuth ferrite (BFO), biomimetic osteogenic hydrogel (BOH).
NMCCs	Cell membrane	CaCO3	Spontaneous	Cancer treatment	22
BSA–Bi2S3–MnO2	BSA	Bi2S3–MnO2	LbL	Cancer treatment	23
MSN–B(OH)2	Yeast cells	MSNs	Bridging	Active ingredient protection	24
TMV@ZIF composites	TMV	ZIF-8	Spontaneous	Active ingredient protection	25
Supra-HeLa cell-ZIF-8	HeLa	ZIF-8	Spontaneous	Active ingredient protection	26
eMIONs	Encapsulation	Fe3O4	Genetic engineering	Cancer treatment	27
MCF-7	PEG	Au NPs	Spontaneous	Cancer treatment	28
Beta cell@CONPs/alginate	Alginate microbeads containing beta cells	CONPs/alginate	LbL	Active ingredient protection	29
C. pyrenoidosa	C. pyrenoidosa	Anaerobic microenvironment	LbL	Active ingredient protection	30
NERBCs	Red blood cells	HAP, Ca10(PO4)6(OH)2	LbL	Active ingredient protection	31
MSNs	Yeast cells	MSNs	LbL	Active ingredient protection	24
Engineered yeast cells (EYCs)	Yeast cells	SiO2	Regulation of intracellular ion concentration	Cancer treatment	32
CaP-OMVs	OMVs	CaP	Spontaneous	Cancer treatment	33
Protein@ZIF-8 nanoparticles	BSA	ZIF-8	Spontaneous	Bioimaging	34
CuS@BSA-HMONs	BSA	CuS	Spontaneous	Cancer treatment	35
GCAH	GOx	CaP	Spontaneous	Cancer treatment	36
GMCD	GM	DVDMS	Spontaneous	Cancer treatment	37
Fe-DNA/GOx@ZIF-8	PolyA20 DNA	ZIF-8	Spontaneous	Cancer treatment	38
Self-mineralizable membranes (HBG)	Bio-Gide® membranes	CaP	Spontaneous	Hard tissue repair	39
BSA/AIEgen@CaCO3	BSA	CaCO3	Spontaneous	Cancer treatment	40
Calcification-inducing polypeptide (CiP)	Cancer cell	CaP	Spontaneous	Cancer treatment	41
Fe4[Fe(CN)6]3, (PB)-CaO2	Cancer cell	Fe(OH)3	Regulation of intracellular ion concentration	Cancer treatment, bioimaging	42
CaP-DOX@Fe^2+-siMCT4-PEG-HA	siMCT4-PEG-HA	ACP	Spontaneous	Cancer treatment	43
DSPE-PEG-ALN, DPA	Cancer cell	CaP	Bridging	Cancer treatment	44
CaP&PB	Prussian blue (PB)	CaP	Bridging hybrid	Cancer treatment	45
GOx-Mn/HA	GOx	CaP	Spontaneous	Cancer treatment	46
ECM/DPSC microspheroids	ECM/DPSC	CaP	Spontaneous	Hard tissue repair	47
BINP	Cancer cell	CaP	Regulation of intracellular ion concentration	Cancer treatment	48
αPDL1@MnO2	α PDL1	MnO2	Spontaneous	Cancer treatment	49
Man-MnO2@OVA nanovaccines	OVA	MnO2	Spontaneous	Cancer treatment	50
UsCCP	Collagen fibrils	CaP	Spontaneous	Hard tissue repair	51
IAV@Mn	IAV	MnP	Spontaneous	Active ingredient protection	52
GC6@cPt ZIF	GOx, CAT	ZIF-8	Spontaneous	Cancer treatment	53
AR-ZS/ID-P	SF	ZIF-8	Spontaneous	Cancer treatment	54
LND-BSA@FePO4	BSA	FePO4	Spontaneous	Cancer treatment	55
ZIF-8@urease	Urease	ZIF-8	Spontaneous	Active ingredient protection	56
PC@CaP	PC	CaP	Spontaneous	Active ingredient protection	57
Biomorphic porous metal chalcogenide hollow nanostructures	Cocci and bacillus	PbS and ZnS	Spontaneous	—	58
Ad5-GFP-CaPi	Ad5	CaP	Spontaneous	Active ingredient protection	59
B-JEV	JEV	CaP	Spontaneous	Active ingredient protection	60
Si-EV71	EV71	SiO2	Spontaneous	Active ingredient protection	61
rAd5-Env/CaP	rAd5	CaP	Spontaneous	Active ingredient protection
ZIF-8/BSA	BSA	ZIF-8	Spontaneous	Active ingredient protection	62
Chlorella@CeO2	Chlorella	CeO2	Spontaneous	Active ingredient protection	63
Yeast-CaP	S. cerevisiae cells	CaP	LbL	Active ingredient protection	64
Yeast@SiO2	Yeast cells	SiO2	LbL	Active ingredient protection	65
BSA/DNA/BSA/nanoAg/BSA/DNA-coated yeast	SaC and Trichoderma asperellum	Gold and silver nanoparticles	LbL	—	66
Silica-coated yeast	S. cerevisiae cell	SiO2	LbL	Active ingredient protection	67
YF-17D/PAH-PSS	YF-17D	PAH-PSS	LbL	Active ingredient protection	68
Yeast@SiO2	Yeast	SiO2	LbL	—	69
Chlorella@SiO2–TiO2	Chlorella	SiO2–TiO2	LbL	Active ingredient protection	70
Cyanobacteria@SiO2	Cyanobacteria	SiO2	LbL	Active ingredient protection	71
LbL-NSCs	NSCs	Gelatin (type A)-alginate	LbL	Active ingredient protection	72
Ca–Au–SaC	Sa	Au NPs	Bridging	—	73
RBC-HPG	RBC	HPG	Bridging	—	74
SaC-GR-Ca–Au	SaC	Ca–GO	Bridging	—	75
Yeast@R4C12R4@SiO2	SaC	SiO2	Bridging	Active ingredient protection	76
PDA-RBCs	RBC	PDA	Bridging	Active ingredient protection	77
Yeast@PN@SiO2	SaC	SiO2	Bridging	Active ingredient protection	78
M. thermoacetica–CdS	Moorella thermoacetica	CdS	Bridging	—	79
Bacterial@PPy	Bacterial	PPy	Bridging	—	80
Cell/bilayered nanoshell	SaC	Au NPs, SiO2	Bridging	Active ingredient protection	81
Paratungstate-mineralized virus	CCMV	Inorganic par tungstate	Regulation of intracellular ion concentration	—	82
A7–pVIII-engineered viruses	M13 bacteriophage	ZnS	Regulation of intracellular ion concentration	—	83
Yeast–CdSe	SaC	CdSe quantum dots	Regulation of intracellular ion concentration	—	84
Yeast–CaCO3	SaC	CaCO3	Regulation of intracellular ion concentration	—	85
nHAP@yeasts	Yeast cells	HAP	Regulation of intracellular ion concentration	—	86
Co–Pt-CCMV	CCMV	Fe–Pt NPs, Co–Pt NPs	Regulation of intracellular ion concentration	—	87
A7-ZnS	M13 bacteriophage	ZnS	Genetic engineering	—	88
TMV2cys	TMV	Metal cluster	Genetic engineering	—	89
M13-Co3O4	M13 virus	Co3O4	Genetic engineering	—	90
Pichia pastoris@SiO2	Pichia pastoris	SiO2	Genetic engineering	—	91
—	M13 bacteriophage	Anhydrous iron phosphate (a-FePO4)	Genetic engineering	—	92
M13-HAP	M13 bacteriophage	HAP	Genetic engineering	Hard tissue repair	93
Virus-templated STO nanowires	M13 bacteriophage	STO, BFO	Genetic engineering	—	94
EV71-W6-CaP	EV71	CaP	Genetic engineering	Active ingredient protection	95
—	Yeast	Magnetite	Genetic engineering	Bioimaging	96
Engineered bacterial cells	E. coli	Magnetite	Genetic engineering	Bioimaging	97
GOx@MIL-53(Fe)@PVP (GMP)	GOx	MIL-53(Fe)	Spontaneous	—	98
Multishell colloidosome	EcN	CaCO3, SiO2, calcium alginate (Alg–Ca) gel	Bridging	—	99
GOD@Cu-ZIF-8	GOx	Cu-ZIF-8	Spontaneous	Cancer treatment	100
BOH	—	Nano-hydroxyapatite	Spontaneous	Hard tissue repair	101
Coated embryo	Zebrafish embryo	CaCO3	LbL	Active ingredient protection	102
Yeast@MnO2	Yeast	MnO2	Spontaneous	Active ingredient protection	103
BioVaccine	ChinDENV2	CaP	Spontaneous	Active ingredient protection	104
CaP-PILP	Polymer-induced liquid-precursor (PILP)	CaP	Spontaneous	Hard tissue repair	105
A-MnO2 NPs	BSA	MnO2	Spontaneous	Cancer treatment	106
^131I-HSA-MnO2	HSA	MnO2	Spontaneous	Cancer treatment	107
—	HeLa	CaP	Spontaneous	Cancer treatment	108
Tri alkoxysilane–TPP	Mitochondria	SiO2	Spontaneous	Cancer treatment	109

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2. Principles and methods of constructing biohybrid materials based on a biomimetic mineralization mechanism

To date, various organisms including yeast, algae, bacteria, viruses and even human cells have successfully employed different methods of modification through biomimetic mineralization mechanisms. This chapter summarizes the basic principles of biomimetic mineralization to construct hybrid organisms, which are mainly divided into spontaneous mineralization, layer-by-layer (LbL) self-assembly mineralization, bridging hybridization mineralization, regulation of intracellular ion concentration mineralization and genetic engineering. This helps us to better understand the mechanisms by which biological organisms produce biominerals and to propose new methods for modifying biological species.

2.1 Spontaneous

Some living organisms or substances in nature, due to their unique surface functional groups such as carboxyl, amino, hydroxyl, etc., can deposit and form a calcium-rich surface layer in an environment rich in Ca²⁺ and other metal cations without any modification, which in turn forms a calcium phosphate (CaP) mineralization layer on the biological surface. This process is called “spontaneous mineralization”.^110,111 Spontaneous mineralization can occur in living organisms such as bacteria and viruses, and can also be used as a principle for modifying bioactive materials.

Most Gram-positive bacterial cell walls contain abundant negatively charged functional groups such as carboxyl groups (R–COOH), phosphate monoester groups (R–OPO₃H₂), amines (R–NH³⁺), and hydroxyl groups (R–OH), which have great potential for inducing mineralization. Based on this, Zhang and co-workers used bacterium (cocci and bacillus) as morph-templates in an environment rich in Pb²⁺, Zn²⁺ and thioacetamide, and the negatively charged functional groups on the surface of cocci and bacillus adsorbed the metal sulfide clusters, PbS and ZnS, formed in the solution and deposited them to form nanoscale metal sulfide covered cell complexes. After using ultrasound to destroy the bacteria, hollow nanostructures of PbS and ZnS were successfully synthesized in biological form (Fig. 2A).⁵⁸ Some viruses contain abundant anionic peptide groups on their surface, which can also be directly biomineralized to modify them.¹¹² For example, adenovirus serotype 5 (Ad5) or Japanese encephalitis vaccine virus (JEV) exhibit strong negative charges under physiological conditions and can take up and concentrate abundant Ca²⁺ by co-culturing with calcium-rich DMEM to increase local supersaturation, thereby inducing the formation of nanoscale CaP mineralization on the virus surface (Fig. 2B).^59,60,113 Tobacco mosaic virus (TMV) has 2130 identical coat proteins (rich in negatively charged functional groups such as carboxyl and amino groups), which are arranged helically around a 4 nm central pore where the viral RNA is located.^114–116 This allows Zn²⁺ to bind and be fixed to the sites on the surface of virus particles resulting in locally high concentrations of Zn²⁺, promoting mineralization processes, and ultimately leading to the formation of a 10–40 nm thick ZIF-8 shell.²⁵

Fig. 2 (A) Schematic illustration of the general controlled synthesis of shape-controllable biomorphic porous metal chalcogenide hollow nanostructures with bacteria as morph-templates.⁵⁸ Copyright © 1990 IOP Publishing. (B) Schematic presentation of in situ mineralization of Ad5 with core–shell structure.⁵⁹ Copyright © 2024 WILLY. (C) Scheme of one-step CeO₂ nanoshell formation on the chlorella cell and the mechanism of UV protection. Copyright © 2017 ACS. (D) Transmission electron microscopy (TEM) micrographs of microtome-sliced native Chlorella and Chlorella@CeO₂.⁶³ Copyright © 2017 ACS.

In addition to bacteria or viruses, research has found that some algae can spontaneously absorb positively charged cerium dioxide nanoparticles (CeO₂ NPs), forming a 40–50 nm thick CeO₂ envelope around the cell. This can be attributed to the fact that the cell wall of algae consists of cellulose, polysaccharides, and glycoproteins, which can provide sufficient binding sites for CeO₂. The nanoparticles bind to the cell surface through non-specific (electrostatic, hydrogen bonding, and hydrophobic) interactions, and form a shell that encloses the cell surface (Fig. 2C and D).⁶³

In addition to living organisms, some biomaterials such as peptides, polysaccharides, proteins and nucleic acids have abundant ion receptors on their surfaces (such as carboxyl, amino, hydroxyl groups, etc.). There is a strong chelating interaction between these ion acceptors and oppositely charged ions such as Ca²⁺ and PO₄³⁻, which can allow the biomaterial to act as a nucleation precursor for minerals, inducing the formation of ore layers on the surface of the biomaterials.¹¹⁷ Inspired by the above biomimetic mechanism, proteins such as glucose oxidase and ferritin can immobilize Ca²⁺ in solution through electrostatic interactions as nucleation sites, and then form a nanoscale CaP shell with PO₄³⁻ in the environment.^36,37,118 The amorphous minerals are unstable in aqueous solution.¹¹⁹ In contrast, they can be kinetically stabilized by proteins in various organisms through interactions between the minerals and the functional groups of proteins; the stabilized amorphous minerals can then be used as precursors of crystalline biominerals or for calcium reservation.¹²⁰ Based on this, Wang and coworkers demonstrated amorphous carbonated calcium phosphate (ACCP)-modified nanoparticles (NPs) and amorphous CaP (ACP) coatings.¹²¹

In addition to water-soluble proteins, non-water-soluble proteins can also serve as templates to induce calcium phosphate mineralization. Zein has an amphiphilic character due to its unusual amino acid sequence which contains high hydrophobic residues, and it is insoluble in water but is readily dispersed in alcohol–water mixtures.¹²² The molecular structure is a helical wheel confirmation with nine homologous repeating units arranged in an antiparallel form stabilized by hydrogen bonds.^123,124 A zein Langmuir monolayer was used as an insoluble plant. After biomimetic mineralization for 1 h, zein films are uniformly covered with continuous calcium phosphate nanosheet networks.¹²⁵

2.2 LbL self-assembly

Since there are not enough mineralization sites on the surface of some biomaterials, it is necessary to modify their surfaces by chemical methods to provide abundant negative charges and promote the formation of mineral layers. One of the most representative methods is LbL self-assembly. LbL self-assembly is a surface modification method in which polyelectrolyte molecules with opposite charges are alternately deposited on the surface of biomaterials through intermolecular interactions (electrostatic force, van der Waals forces, hydrophobic/hydrophilic and hydrogen bonds).^126,127 This strategy can change the charge density on the surface of biomaterials and endow them with abundant mineralization sites, inducing the occurrence of biomineralization.

The negative charge density on the surface of yeast cell walls is relatively low, and even in an environment rich in Ca²⁺, a mineralization layer cannot form.¹²⁸ For this reason, Tang's group used the LbL self-assembly for the first time in 2008 to improve the mineralization ability of yeast cells.⁶⁴ They used two polyelectrolytes with opposite charges, poly(diallyl dimethylammonium chloride) (PDADMAC, positively charged) and poly(acrylic sodium) (PAA, negatively charged), as modifiers. Firstly, the positively charged PDDMAC is adsorbed onto the negatively charged yeast cell wall, and forms a positively charged surface layer. By adding negatively charged PAA, it can adsorb onto the surface of PDDMAC to reverse the surface charge, and it contains abundant carboxylic acid groups. After 8 repetitions, the surface of the yeast cell wall can recruit and bind free Ca²⁺ from the environment to form a 700 ± 50 nm CaP shell on the surface of the yeast cell.⁶⁴ In addition to PDADMAC and PAA, other synthetic polymers such as poly(styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) can also be used for the modification of living organisms.^129,130 PAH can attach itself around viruses through electrostatic interactions, and form a positively charged surface layer (the ζ potential is +67 mV). A negatively charged polyelectrolyte PSS was introduced to form a surface layer rich in sulfonic acid groups on the surface of the virus, resulting in a virus/PAH-PSS core/shell structure (Fig. 3A).⁶⁸ In addition to modifying negatively charged materials to adsorb Ca²⁺, positively charged materials on the surface of living organisms can also be modified to adsorb silicate derivatives and form a 50 nm thick silicon dioxide (SiO₂) shell.^131,132 Choi's group alternately applies cationic polyelectrolyte PDADMA and the anionic polyelectrolyte PSS to the surface of yeast cells. The LbL self-assembly envelope starts with positively charged PDADMA (the yeast cell wall is negatively charged) and also ends with PDADMA (which provides binding sites for negatively charged silicate derivatives), promoting the formation of silicon minerals (Fig. 3B).⁶⁹

Fig. 3 (A) Preparation of a YF-17D/PAH-PSS hybrid complex and direct TEM observation of YF-17D/PAH-PSS without stain.⁶⁸ Copyright © 2010 Wiley-VCH. (B) Procedure for silica encapsulation of individual yeast cells. Alternate LbL deposition of polycations and polyanions onto the yeast surface of yeast preceded biomimetic silica formation.⁶⁵ Copyright © 2009 WLEY-VCH. (C) The illustration of the major steps involved in the LbL encapsulation.⁷² Copyright © 2015 ACS.

As the polycation layer directly contacts the cell membrane, most polycations (PDADMAC, polyethyleneimine (PEI), polylysine (PLL)) can cause membrane perforation in mammalian cells during the LbL self-assembly process.⁶⁴ Natural polymers (alginates, gelatin, hyaluronic acid, etc.) have the advantages of good biocompatibility and easy availability of raw materials and are widely used to modify biomaterials.^59,60,113 Kong and coworkers have applied this technology to the encapsulation of neural stem cells (NSCs) (Fig. 3C).⁷² By selecting biodegradable gelatin (type A) and alginate as components of the LBL layer, the negatively charged NSCs are first incubated with positively charged gelatin to form a positively charged surface layer and then incubated with negatively charged alginate to form a negatively charged surface layer. After repetition, 3 layers of LBL-encapsulated NSCs (with a thickness of about 6 nm) are formed on the NSCs.

At present, LBL self-assembly mineralization is used to induce mineralization in cells such as fungi, bacteria, viruses, etc. However, repeated separation and purification operations such as centrifugation and washing are required during the preparation process, inevitably causing physical damage to the cells. Therefore, this method is mainly suitable for modifying rigid cells with cell walls (such as yeast cells), while it is not suitable for cells without cell walls (mammalian cells).¹³³

2.3 “Bridging” hybrid mineralization

The use of LBL self-assembly mineralization requires the repeated deposition of polyelectrolytes onto the surface of biomaterials, which takes a certain amount of time and the preparation process is relatively laborious. Therefore, materials such as peptides,⁷⁶ nanoparticles,⁸¹ polymers and polyelectrolytes⁷⁸ can be used for a one-step modification to enrich the mineralization sites at the interface of biomaterials to promote biomimetic mineralization on biomaterials.

Some polymers with good biocompatibility can serve as “bridges”. Polydopamine (PDA) has abundant catechol groups that promote mineralization by binding and accumulating Ca²⁺ at the interface.¹³⁴ Huang's group constructed a sandwich structure on the surface of Chlorella vulgaris cells, with PDA serving as a “bridge” connecting the cells, promoting adhesion between the coated cells and various matrices, which is important for the subsequent modification of the coated cells. Moreover, PDA can be regarded as a surface modifier to regulate the interfacial energy of the substrate.¹³⁵ Gu's group used PDA as a surface modifier to modify collagen fibers as well as the solid–liquid interface; achieving dentin remineralization.¹³⁶ Through the interaction between PDA and amines or thiols, laccase on the cell surface is modified and forms a nanoscale sandwich-like structure.³⁰ Poly(norepinephrine) (PN) is a dopamine derivative with abundant hydroxyl groups, and compared to PDA, PN has better cell compatibility. Choi's group formed a PN layer on the surface of yeast cells by culturing PN with yeast cells. Then, the hydroquinone in the PN layer is conjugated with the amine group of PEI by nucleophilic 1,4 addition, and a layer of PEI is modified on the PN layer. Finally, the modified yeast cells were incubated in a solution of silica derivatives using PEI as a catalytic template. Through electrostatic interaction, the silica derivatives accumulated on the surface of the PEI-modified yeast cells and formed a biomimetic silicon shell with a thickness of about 30 nm (Fig. 4A and B).⁷⁸

Fig. 4 (A) Schematic representation of the artificial shell, composed of organic poly(norepinephrine) (PN) and inorganic silica layers (yeast^WT: wild-type yeast; yeast^ECP: encapsulated yeast).⁷⁸ Copyright © 2015 RSC. (B) TEM micrographs of the microtome-sliced yeast^ECP.⁷⁸ Copyright © 2015 RSC. (C) Au NPs are functionalized with Ca²⁺ transforming them into branched-chain assemblies. Subsequently, the Ca–Au nanoparticles are deposited onto the GO sheets forming GO–Ca–Au assemblies that are reduced to form GR–Ca–Au. Yeast cells, SaC, are then interfaced with the GR–Ca–Au sheets via Ca²⁺ functionalization.⁷⁵ Copyright © 2011 ACS. (D) A high-angle annular dark field (HAADF) STEM image of M. thermoacetica–CdS hybrids, showing clusters across the entire cell surface (scale bar: 500 nm).⁷⁹ Copyright © 2016 AAAS.

In addition, some metal cations can also act as “bridges” to promote the mineralization of biomaterials. Due to the positive charge properties of Ca²⁺, it can adsorb to negatively charged biological material surfaces through electrostatic interactions. In addition, Ca²⁺ have a positive valence and can act as a “bridge” between two negatively charged ions.¹³³ Utilizing the bridging effect of Ca²⁺, Maheshwari's group constructed a graphene-coated yeast cell. Ca²⁺ combined with citrate-functionalized gold nanoparticles (Au NPs, 12 nm) to form Ca–Au nanoparticles. Subsequently, Ca–Au nanoparticles were combined with graphene oxide (GO) due to the interaction between carboxyl and hydroxyl groups and Ca²⁺ to form GO–Ca–Au. Finally, yeast cells were immersed in a mixed solution of GO–Ca–Au, and Ca²⁺ served as an interface between the GR sheets and the yeast cells, allowing the yeast cells to be coated with a layer of graphene material (Fig. 4C).⁷⁵ When Ca²⁺ are added to a polyanionic solution, they immediately form a polyelectrolyte calcium aggregate,^137,138 which can act as a “bridge” to drive the assembly of amorphous calcium carbonate (ACC). Fu and coworkers proposed a polyelectrolyte–Ca complex pre-precursor (PCCP) process based on electrostatic attraction, osmotic pressure, and capillary effect for the rapid biomimetic mineralization of collagen. The liquid-like electropositive polyaspartic acid (PAsp)–Ca complexes along with free Ca²⁺ infiltrate electronegative collagen fibrils. The PAsp–Ca complexes are immobilized within the fibrils via chelation and hydrogen bonds, and outward movement of free Ca²⁺ is prevented while phosphate and hydroxide are recruited through electrostatic attractions. The PAsp–Ca complexes aggregate with free calcium ions to form calcium rich regions in the fibers. These regions can recruit phosphate and hydroxide ions through electrostatic attraction, after which ACP immediately forms and gradually crystallizes.¹³⁹ Other metal cations, such as chromium ions, can also act as bridges. The surface of Moorella thermoacetica can accumulate Cd²⁺, and under the action of light and cysteine, a shell of CdS nanoparticles then forms on the cell surface (Fig. 4D).⁷⁹

Peptides can also serve as “bridges”. Choi's group has designed a peptide (sequence: (RKK)₄D₈ (R: arginine; K: lysine; D: aspartic acid)) for the surface mineralization of Chlorella vulgaris cells. The positive part R of (RKK)₄D₈ is adsorbed to the negatively charged cell surface through electrostatic interaction, and its negative part D can then induce the deposition of silica (SiO₂ precursor) and Ti-BALDH (TiO₂ precursor) onto Chlorella vulgaris cells and form a SiO₂–TiO₂ nanoshell.⁷⁰ Yang's group constructed a positively charged peptide (sequence R₄C₁₂R₄ (R: arginine; C: cysteine)) to induce surface silicification of yeast cells. The peptide first adsorbs to the surface of yeast cells through electrostatic interaction (with a positive R sequence) and then introduces tetraethyl orthosilicate (TEOS, SiO₂ precursor). Under the catalysis of R₄C₁₂R₄ (cysteine has silicon-like protein-a activity), a silicon shell with a thickness of about 80 nm is formed on the surface of yeast cells.⁷⁶

In addition, other substances can act as “bridges”. Su and coworkers have used a bio-hybrid layer of Au NPs and L-cysteine as a “bridge” to construct yeast cells encapsulated in a double-layered nanoshell. Specifically, yeast cells are first co-installed with a solution of Au NPs modified with L-cysteine, and a biological hybrid layer is formed on the surface of the yeast cells by electrostatic interaction. Amino-modified Au NPs form hydrogen bonds with polysaccharide hydroxyl groups on the surface of yeast cells, without being taken up by the cells. Subsequently, yeast cells were exposed to suspended amorphous SiO₂, and the functional groups on the cell surface interacted with the hydroxyl groups of SiO₂ and formed a double-layer nanoshell on the surface of the yeast cells.⁸¹ The click reaction of phenylboronic acid can be used to generate covalent bonds with cis-diol. The cell wall of yeast cells consists mainly of polysaccharides. On this basis, Su and coworkers constructed a SiO₂ layer of 100–150 nm on the surface of yeast cells. Specifically, B(OH)₂ is applied to mesoporous SiO₂ nanoparticles (MSNs) through a Schiff-base reaction to form MSN–B(OH)₂. Subsequently, MSN–B(OH)₂ is co-incubated with yeast cells, and MSNs are rapidly grafted onto the hydroxyl groups of polysaccharides on the cell surface, forming a nanoscale SiO₂ shell on the cell surface.²⁴ Phytic acid, also known as inositol hex phosphate (IP6), has six phosphate groups and a strong negative charge, which can significantly chelate Ca²⁺ and act as a crosslinking agent for protein assembly, thereby inducing collagen fiber mineralization. Gu and coworkers combine phytic acid with collagen fibers through hydrogen bonding. IP6 can enhance the attraction to mineral ions, and create a local supersaturated environment for the nucleation and growth of HAP crystals, and improve ACP penetration inside collagen fibers through interface regulation.¹⁴⁰ Besides, Tang's group revealed that citrate molecules reduce the interfacial energy between collagen and ACP, and facilitate the heterogeneous formation of ACP precursors on collagen and subsequent intrafibrillar mineralization by a wetting effect.¹⁴¹

In contrast to LbL self-assembly mineralization, this method has simpler steps, takes less time and does not require repeated centrifugal washing of the biological materials, thus avoiding their mechanical damage to a certain extent. However, this method is suitable for the modification of biomaterials with high charge density and has certain limitations.

2.4 Regulation of intracellular ion concentration

Some organisms (such as bacteria, fungi, etc.) can produce intracellular minerals, and certain macromolecules in the organism play a crucial role in the process of biomineralization (certain reducing proteins).¹⁴² However, due to the low concentration of ions associated with mineralization in biomaterials, these biomolecules cannot function well. Human intervention in the intracellular ion concentration can trigger mineral formation.

Yeast cells can self-regulate the balance between internal and external ions, making it difficult to produce minerals within the cells under normal physiological conditions. By introducing excessive metal ions into the culture environment, this balance can be disturbed and the corresponding minerals can be produced within the cells. Winge's group first synthesized nanoscale cadmium sulfide (CdS) quantum semiconductor microcrystals within yeast cells in 1989.¹⁴³ By co-incubating yeast cells with cadmium salts, the short chelating peptide (γ-Glu-Cys)_n-Gly controlled the nucleation and growth of CdS microcrystals, forming peptide-capped particles with a diameter of 20 Å inside the cells. Under the action of γ-glutamyl peptides, Candida albicans and S. pombe interact with cadmium salts and chelate chromium ions in the cytoplasm, and a γ-glutamyl peptide complex is formed on the glutamyl peptide segment, which forms a cytoplasmic metal thiocyanate peptide complex with cellular sulfides, thereby forming nanoscale CdS quantum semiconductor microcrystals within the cell. Based on this, some similar studies investigated the biosynthesis of other minerals.^{83,84,144–146} Yuan and coworkers reported a method for producing CaCO₃ nanoparticles in yeast cells.⁸⁵ Specifically, yeast cells are co-cultured with maltose to produce a large amount of carbon dioxide (CO₂) by respiration. Then, a supersaturated calcium hydroxide solution is added to create an alkaline environment, and CO₂ is converted into CO₃²⁻. After Ca²⁺ enters the cells, they can interact with intracellular proteins or polysaccharides through electrostatic interactions, providing active sites for subsequent mineralization. Subsequently, excess CO₃²⁻ and Ca²⁺ can form stable CaCO₃ crystals in yeast cells, resulting in functionalized cells with CaCO₃ scaffolds under normal physiological conditions (Fig. 5A and B). In addition to CaCO₃, Yang's group produced hydroxyapatite on a nanoscale (3 nm) in yeast cells. By co-incubating yeast cells with CaCl₂ solution for 24 hours, Ca²⁺ from the environment can penetrate the cell membrane and enter the interior of the yeast cells. The cells were then collected and co-incubated with PO₄³⁻ for 24 hours. During this period, PO₄³⁻ can penetrate the cell membrane and enter the interior of yeast cells. In the alkaline environment of Na₃PO₄, Ca²⁺ and PO₄³⁻ can interact and form stable nanoscale hydroxyapatite (Fig. 5C).⁸⁶ Based on this, Lu and coworkers induced the formation of nanoengineered red blood cells (NERBCs).³¹ Ca²⁺ solution and phosphate buffered saline (PBS, pH = 9) were successively added to the erythrocyte solution, and the mixture was incubated. During which PO₄³⁻ and OH⁻ crossed the RBC cell membrane and entered the cells, thus leading to the generation of the NERBCs.

Fig. 5 (A) Formation mechanism of the functionalized cell with endogenous production of a CaCO₃ nanoparticle scaffold.¹³⁰ Copyright © 2011 WILEY-VCH. (B) Scanning electron micrograph of the functionalized cells.¹³⁰ Copyright © 2011 WILEY-VCH. (C) Formation mechanism of hydroxide hydroxyapatite (HAP) mineralized yeast cells and functionalized mineralized yeast cells, and their potential application in tumor-targeted delivery.⁶⁸ Copyright © 2024 RSC.

In addition to cells, some viruses can also achieve internal mineralization by artificially interfering with internal ion concentrations. Young's group formed nanoscale tungstate crystals (approximately 150 Å) within the virus by regulating the pH of the system.⁸² They used the cowpea chlorotic mottle virus (CCMV) as a mineralization model. This virus consists of 180 identical subunits of the coat protein arranged on an icosahedral lattice. Each subunit of the coat protein has at least 9 alkaline residues (arginine and lysine) inside the cavity. This creates a positively charged inner cavity surface that forms an interface for the nucleation and growth of inorganic crystals.¹⁴⁷ The reversible expansion of CCMV can be controlled by adjusting the pH value. Under expansion conditions (pH > 6.5), the virus particles expand along the pseudo-three-fold axis, and form 60 independent pores (with a diameter of 20 Å) in the protein coat, increasing the virus volume by 10% and allowing molecular exchange in the virus cavity and the culture environment. In the non-swollen state (pH < 6.5), no such exchange takes place.¹⁴⁸ Based on this, Young's group induced the oligomerization of aqueous mononuclear tungstate species (WO₂⁴⁻) to form para-tungstate polyanions (H₂W₁₂O₁₀⁴²⁻) by lowering the pH. The virus is purified by centrifugation to remove the viral RNA, and then the empty virus body is co-incubated with inorganic precursor ions. Under swelling conditions (pH > 6.5), the viral cavity allows inorganic ions to enter. After incubation, the protein pores in the viral envelope are closed by lowering the pH so that parenting state ions can be trapped in the virus body and tungstate crystals eventually form in the virus. In addition, Schwarzacher's group controls the opening and closing of ion channels on the CCMV virus shell by changing the pH and metal ion concentration of the solution and adding NaBH₄ to reduce [PtCl₄]⁻ to pure Pt NPs. The size of nanoclusters is limited to within 18 nm by the inner diameter of the CCMV virus shell. Interestingly, Co–Pt and Fe–Pt alloy nanoclusters can be synthesized by adding additional metal ions (Co or Fe), and the atomic ratio of bimetallic NPs can be tuned by controlling the proportion of ion sources in the synthesis solution.⁸⁷

2.5 Genetic engineering

Some organisms in nature contain genes that regulate proteins associated with biomineralization. In organisms lacking this regulatory gene, the insertion of mineralization-related protein genes into the organism through genetic engineering can endow the organism with the ability to induce mineralization itself. Compared to chemical modification, genetic engineering can provide organisms with a heritable mineralization capacity.

The combination of different metals with titanium on the outer shell of the M13 bacteriophage can cause the formation of different mineral layers. Belcher's group has long used genetically modified M13 bacteriophages to induce the growth of inorganic nanomaterials and has obtained many inorganic nanomaterials with unique morphologies and structures. In 2002, the Belcher's group first used genetically engineered M13 bacteriophages to directly perform quantum dot-assisted biological composite structure sorting at multiple length scales.⁸⁸ By screening the major selective peptide binding motifs (Cys-Asn-Asn-Pro Met-His-Gln-Asn Cys, A7), which have specific recognition for the surface of ZnS crystals, and modifying them on the surface of a bacteriophage to form an A7 bacteriophage; then it was suspended in a ZnS precursor solution to form a rod-shaped A7 bacteriophage ZnS nanocrystal (A7-ZnS) liquid crystal. The research has found that due to genetic selection in peptide recognition, the formation of different types of inorganic nanocrystals can be easily regulated and arranged in 3D layered structures (Fig. 6A).⁸⁸ Mao's group found that it can form in the free β-sheet structure when structural peptides and peptides that promote hydroxyapatite formation fuse with the cell wall of the M13 phage, these two peptides can still form a β-sheet structure, and the structure further drives the aggregation of bacteriophages into bundles, which is beneficial for HAP nucleation and growth. In this study, dentin matrix protein 1 (DMP-1) derived peptides ₃₈₆ESQES₃₉₀ (npE) and ₄₁₅QESQSQDS₄₂₂ (pQ) were selected, which can form a β-sheet structure in a Ca²⁺ environment and further self-assemble into nanofibers. Integration of these two peptides into the cell wall of the M13 phage, resulted in an E phage and Q phage. The formation of intermolecular interactions between peptides on neighboring bacteriophage β-structures, drives the self-assembly of phages into bundles to simulate collagen fibers in natural bones. Precise nucleation of HAP crystals from supersaturated HAP solutions to HAP nucleation in an engineered bacteriophage bundle β-structure (Fig. 6B).⁹³

Fig. 6 (A) Schematic diagram of the process used to generate nanocrystal alignment by the phage display method.⁸⁸ Copyright © 2002 AAAS. (B) TEM image of Wild-Type M13 phages (left); display of a foreign peptide on the side wall of the M13 phage by inserting the peptide into the N-terminus of the major coat protein (pVIII) of the M13 phage (middle); 3D model of pVIII (PDB ID: lifd) (right).⁹³ Copyright © 2011 ACS. (C) Schematic of the heterologous expression of surface-modified encapsulin variants loaded with endogenous cargo proteins.¹⁴⁹ Copyright © 2008 Nature Research. (D) Genetic constructs encoding the shell protein A (light blue) with a FLAG-tag as C-terminal surface modification as well as individual Myc-tagged cargo proteins (red) B, C, and D that can also be combined in a multi-gene expression construct (BCDP2A).¹⁴⁹ Copyright © 2008 Nature Research.

In addition, the phosphate chelator (N6p) exerts its role as a CaP-binding peptide via phosphate chelator domains (SVKRGTSVG and VGMKPSP).¹⁵⁰ The calcium chelator (NWp) is a peptide derived from the N-terminal 15-residue fragment of salivary streptococcus (a high-affinity CaP protein), while another calcium chelator (W6p) is a peptide derived from the N-terminal 15-residue fragment of salivary streptococcus and DMP.¹⁵⁰ By inserting these peptides on the surface of human enterovirus 71 (EV71) particles β-(BC)-ring on the amino acid sites between 100 and 101, the virus can spontaneously induce the formation of a nanoscale CaP shell (5–10 nm) (Fig. 6C and D).⁹⁵

It is interesting to note that in eukaryotic cells, local biomimetic mineralization within the cell can be controlled by genetic engineering, resulting in multifunctional reaction chambers within the cell.¹⁴⁹ Genetic engineering of eukaryotic cell compartmentalization is achieved by heterologous expression of the bacterial envelope protein shell and cargo protein to enable closed enzymatic reactions and size-limited biomineralization of metals. The shell protein (EncA) of Staphylococcus aureus automatically assembles into a nanochamber within mammalian cells which can be targeted by natural (EncB, C, D) and engineered cargo proteins, thereby achieving local bimolecular fluorescence and enzyme complementarity (Fig. 6C and D).

With advances in molecular biology, genetic engineering has become a powerful tool for the manipulation of organisms at the genetic level. With this approach, peptides related to biomineralization can be genetically bound to the surface of the virus to trigger spontaneous virus mineralization. However, returning such genetically engineered organisms into nature can lead to “genetic pollution” and spell disaster for both humanity and the planet.

3. Biomedical applications of biohybrid materials

3.1 Active ingredient protection

Due to the complexity of the environment, biological organisms are susceptible to external influences. Following the example of eggshells, biomimetic mineralized artificial shells are applied to the outside of biological organisms, similar to an “armor layer” on the surface of biological materials, which enables them to resist changes in the external environment and thus provide protection.

3.1.1 Resistant to ultraviolet radiation. Photosynthetic microorganisms (such as blue-green algae, green algae, diatoms, etc.) play an important role in the development of renewable energies. Each year, around 25 gigatons of carbon dioxide are sequestered worldwide by cyanobacteria as energy-intensive substances.¹⁵¹ Blue bacteria are found in almost all terrestrial and aquatic habitats and account for 20–30% of the Earth's photosynthetic productivity.¹⁵² Hence, the role of blue-green algae is critical to addressing growing energy demands and environmental challenges. Unfortunately, microorganisms are susceptible to external environmental influences on photosynthesis, such as blue-green algae, which are highly sensitive to intense light.^153,154 Ultraviolet radiation (UV) from sunlight can inhibit their photosynthesis, significantly impacting the activity of relevant enzymes, causing DNA damage, diminishing photosynthetic pigments, and even harming the protein–pigment complexes' PSII structure, ultimately leading to a decrease in photosynthetic efficiency.^155–158 Therefore, photoinhibition is one of the main causes of biomass loss. How to mitigate the inhibitory effect of strong light plays an important role in increasing photosynthetic products.

The shell of diatoms is a complex nanostructured shell of SiO₂, which provides mechanical protection and photon action. Inspired by diatoms, researchers attempted to apply artificial silicon shells to the surface of blue-green algae cells to mitigate photoinhibition and improve photosynthesis efficiency. Tang and coworkers introduced a layer of SiO₂ shell (called cyanobacteria@SiO₂) into unicellular cyanobacterium (Synechocystis sp. strain PCC 6803). After mineralization, the activity of photosynthetic pigments in cyanobacteria@SiO₂ still exists in native cyanobacteria. Biological SiO₂ can reduce light transmission, so that blue-green algae@SiO₂ exhibit higher photosynthetic activity than natural blue-green algae under strong light irradiation.⁷¹

However, artificially silicified blue-green algae are relatively complex and time-consuming to make. Other biomimetic mineralization methods, such as particle binding and heterogeneous nucleation, require a high density of ion receptors on the cell surface.¹³³ However, excessive ion treatment can lead to damage to the algae.^159,160 To protect algae from UV damage, a biocompatible shell with a UV filtering performance should be designed and constructed reasonably. In addition, the preparation process should take place under physiological conditions and be simple without causing additional damage to the cells of the blue-green algae. Cerium oxide nanoparticles (CeO₂ NPs) can be used as UV filter materials and have good biocompatibility.¹⁶¹ Tang's group reported a one-step method for producing functional CeO₂ complexes from algae (called Chlorella@CeO₂). The method of using this complex can ensure that algae can photosynthesize under UV. Under the artificial UVB irradiation system, the natural Chlorella cells were inactivated, and the photosynthetic activity decreased sharply in the first 12 hours (from 0.74 to 0.16), further decreasing to 0.10 after 24 hours (Fig. 7A). In contrast, the linear photosynthetic electron transfer rate (ETR (II)) of Chlorella@CeO₂ remained at a relatively high level (57.97–45.93 μmol m⁻² s⁻¹) and displayed a significantly higher survival ability (Fig. 7B).⁶³

Fig. 7 (A) The maximum quantum yield (F_v/F_m) of PSII after exposure under 0.3 mW cm⁻² UVB radiation (n ≥ 5).^63,162 Copyright © 2017 ACS. (B) Photosynthetic electron transfer rate (ETR) of PSII after exposure under 0.3 mW cm⁻² UVB radiation (n ≥ 5).⁶³ Copyright © 2017 ACS. (C) Schematic illustration of the protection by shell engineering.⁶³ Copyright © 2017 ACS. (D) Hatchability of the bare embryos and the coated ones under different dosage of UVB radiation.¹⁰² Copyright © 2010 ACS. (E) Deformity percentage of embryos under different UVB doses after a short-term exposure.¹⁰² Copyright © 2010 PLOS. (F) In situ biomineralization creates an egg-like shell on vaccine particles to improve their thermostability. Different from the bare vaccine (squares), the biomineralized vaccine (red circles) can be stored at ambient temperature without refrigeration for up to a week and retain biological activity both in vitro (see graph), as well as in a mouse model.⁶⁰ Copyright © 2012 WILEY-VCH. (G) Pre-immunized mice were intravenously injected with Ad5-Luc (left) and Ad5-Luc-CaPi (right), and Luc production was tested by in vivo imaging on day 1, 2, 4, 6, and 9, respectively. The capacity of Luc production was shown by bioluminescence intensity.⁵⁹ Copyright © 2012 WILEY-VCH. (H) Dual-functional biomineral–vaccine core–shell nanohybrids are obtained using rAd5as templates, which efficiently masks the neutralizing epitope of vaccines and preserve their original immunogenicity.¹¹³ Copyright © 2015 WILEY-VCH.

Intense UV can also have negative effects on other marine organisms, such as zebrafish, since the increased radiation inhibits embryonic development.^163,164 Inspired by biomineralization, Wang's group used rare earth material lanthanide phosphate (LnPO₄) as a component of cell coating to reduce UV penetration and protect the development of zebrafish embryos (Fig. 7C–E).¹⁰²

3.1.2 Resistant to heat. High temperatures can cause conformational changes in proteins, leading to their inactivation. Therefore, many biological substances (such as proteins, blood, vaccines, etc.) are stored in a refrigerated environment. However, storing them at low temperatures is both difficult and expensive, especially in developing countries that lack refrigeration infrastructure. Data suggest that maintaining a cold chain accounts for 80% of the financial costs of immunization projects, estimated at 200 to 300 million dollars per year.¹⁶⁵ Therefore, the production of heat-stable vaccines is beneficial to reduce the waste of resources, ensure efficacy and preserve the vaccines even in the case of supply chain disruptions at low temperatures. Wang's group proposed a new BVSE concept in which viruses with CaP shells are modified by in situ biomineralization. They used Ad5 as a model virus and constructed an Ad5 virus vaccine that was wrapped in a CaP shell by electrostatic interactions between high-density anions on the virus surface and metal cations in the environment. This shell is heat-resistant and can maintain the stability of the virus at room temperature.⁶¹ Taking inspiration from eggshells, Tang's group prepared a JEV wrapped in a CaP shell with good thermal stability.⁶⁰ Mineralization treatment has not changed the original biological activity and infectious function of the vaccine, but it has given the vaccine good thermal stability so that storage at room temperature is achievable. According to the standards of the World Health Organization, the vaccine can be stored in liquid form at 26 °C for one week and can be effectively used for one day even at high temperatures of 37 °C (Fig. 7E). The introduction of vaccine shells can protect vaccines from direct interaction with aqueous solutions, and protect viral proteins from heat inactivation or damage. In addition, the shell can form electrostatic interactions with viral proteins through the interaction between multivalent Ca²⁺ or phosphate ions and polar amino acids, which can improve the stability of protein structure and the interaction between protein subunits.⁶⁰ However, some viruses lack functional groups that induce CaP mineralization on their surface, making it difficult to form mineral shells on the virus surface by direct mineralization. Wang's group can induce CaP mineralization onto the surface of the EV71 vaccine under physiological conditions by introducing gene fragments of nucleating peptides into the vaccine sequence.⁹⁵ Similarly, CaP coatings are also used to improve the thermal stability of virus-like particles (VLPs) of the foot-and-mouth disease virus (FMDV).¹⁶⁶ Mineralized VLPs can be stably stored at 24 °C and 37 °C for 13 and 11 days, respectively. Animal studies have shown that mineralized VLPs effectively activate dendritic cells (DCs) to overexpress related immune factors, migrate to secondary lymphoid tissue, and activate specific T-cell responses, resulting in unaltered immunogenicity.

In nature, archaea and extreme microorganisms use amorphous SiO₂ as a protective biogenic mineral and exhibit considerable heat resistance. Wang's group generates thermally stable viruses by introducing artificially hydrated SiO₂ onto EV71. Mechanism studies have shown that amorphous SiO₂ nanoclusters stabilize the internal virus structure by forming layers that restrict molecular mobility and act as physical and chemical nano anchors. Similar to thermophilic organisms, silicified viruses survive longer at high temperatures than their wild-type relatives. The virus inactivation test showed that external hydration of modified SiO₂ at room temperature prolonged the infectivity of the virus 10 times, and it can be stored at room temperature for 35 days.⁶¹ However, in viruses that do not have mineralized active sites on their surface, active functional groups can be introduced to their surface. Wang's group modifies PEI on the surface of the viral vaccine and builds a mixed coating of SiO₂ and PEI around the vaccine to achieve surface silicification and significantly improve the thermal stability of the vaccine.¹⁶⁷

3.1.3 Biological invisibility. Molecular recognition is the specific recognition interaction between receptor–ligands, antigens–antibodies, DNA–proteins, sugar–lectins, RNA–ribosomes, and other substances. It plays an important role in biological systems, helping to transmit signals and preventing external invasion of organisms.^168–170 For example, the human body's immune system is an important line of defense against external damage. When foreign substances invade, they are easily eliminated by the mononuclear macrophage phagocytosis system, kidney, liver, spleen and other immune systems.¹⁷¹ Unfortunately, some biomaterials are recognized and eliminated by the immune system upon entering the body, which limits the application of biomaterials. A similar study has shown that viral vectors can effectively deliver genes into human cells with high efficiency.^172,173 However, the body's immune system quickly recognizes and eliminates the virus due to its interaction with specific biomolecules in the plasma when the viral vector is introduced into the body.¹⁷⁴ Therefore, the use of biomineralized virus surfaces to hide the recognition sites on the virus surface can help prolong the circulation time of virus vectors in the human body.

The efficient infection rate of Ad5 virus requires is highly cellular primary Coxsackievirus and adenovirus receptor (CAR) dependent, which is invalid for CAR-deficient cells.¹⁷⁵ The specific hepatic tropism of Ad5 prevents the transmission of the virus to other therapeutic tissues.¹⁷⁶ In the human population, pre-existing immunity to Ad5 may greatly limit the immunogenicity and clinical application of recombinant Ad5 as a vector vaccine.¹⁷⁷ Therefore, there are difficulties in the use of Ad5 as a viral vector. Tang's group developed CaP shell-modified Ad5 virus modified with a CaP shell.⁵⁹ Research has shown that biomineralized Ad5 viruses can be effectively transfected into CAR-deficient cells. Once injected into the body, they can prevent specific antibodies from recognizing the virus and evade neutralizing antibodies under biological conditions, allowing systemic administration of the virus in relatively low doses under pre-immune conditions (Fig. 7G).⁵⁹ Based on this, the recombinant adenovirus serotype 5 (rAd5) vector expressing simian immunodeficiency virus (SIV) envelope protein (rAd5-Env) is in situ biomineralized to obtain vaccine-material hybrids with a biodegradable core–shell structure which can mask the surface of the vaccine and preserve their original activity. This kind of shielded vaccine is able to evade the preexisting anti-Ad5 immunity, leading to boosted Env-specific T cell responses. This mineralized vaccine can also evade preexisting anti-Ad5 immunity, leading to boosted Env-specific T cell responses.¹¹³ By acquiring CaP through in situ mineralization, mineralized dengue virus (DENV) can avoid detection by existing antibodies, successfully preventing both in vitro and in vivo infections. Meanwhile, due to the pH-responsive nature of CaP, mineralized vaccines can spontaneously degrade and restore immunogenicity within cells (Fig. 7H).¹⁷⁸ Additionally, Tang's group utilized CaP mineralization modification for nasal vaccination and dengue virus modification, achieving immunity to pre-existing antibodies in the body. They further applied the concept of “biomineralization-based virus shell engineering” to achieve “biological invisibility”.^104,178

The first successful human blood transfusion took place in the 17th century. By 1901, modern transfusion medicine had gradually evolved into a standard treatment method.¹⁷⁹ Currently, although approximately 90 million units of red blood cells can be collected annually, blood type mismatch is the most critical issue in transfusion medicine, especially for some rare blood types such as RhD negative.¹⁸⁰ Corresponding antigens on the surface of red blood cells, and antibodies in the plasma of blood donors will recognize the antigens on the surface of red blood cells from blood donors. If the blood types do not match, the antibodies will identify them as “foreign invaders” and attack them, with serious consequences, even fatal.¹⁸¹ Tang's group proposed a cell engineering approach based on PDA chemistry to prepare universal red blood cells. By using PDA to protect red blood cell surface antigens, this method not only prevents coagulation effects but also has no negative impact on the structure, function, and survival ability of red blood cells.⁷⁷ This method offers a new approach to enhancing red blood cells, particularly for emergency transfusions of rare ABO subgroups. However, there is still a long journey ahead before clinical implementation.

3.2 Cancer treatment

Due to the high mortality rate and limited therapeutic effects of cancer, it is considered the most challenging disease in humans. With the development of nanotechnology, various biohybrid materials based on biomimetic mineralization have been created for the diagnosis and treatment of tumors. Apart from their benefits like good biocompatibility and acid-responsive degradation, biohybrid materials inspired by biomineralization also possess unique optical, magnetic, and thermal properties. These properties contribute to the development of in vitro control systems for more effective integrated tumor diagnosis and treatment.

3.2.1 Drug delivery. In recent years, more and more researchers have come to realize that tumors and the tumor microenvironment (TME) are inseparable entities. Treatment strategies targeting the TME have become a promising approach for cancer treatment, as the TME plays a crucial role in regulating tumor growth. Tumors and the TME are often described as having a “seed” and “soil” relationship.¹⁸² Hypoxia and low pH are common microenvironmental features in malignant solid tumors. These conditions not only promote tumor invasion and metastasis but also have adverse effects on the function of immune cells.¹⁸³ In solid tumors, due to the rapid growth of tumor tissue, but the incomplete internal vascular system of the tissue, this can lead to insufficient oxygen supply in the tumor tissue, leading to an overall hypoxic TME. Insufficient oxygen supply forces tumor cells to rely on anaerobic glycolysis for energy metabolism (known as the Warburg effect), resulting in lactic acid accumulation. Simultaneously, ion exchange proteins on the membrane of tumor cells continuously transport intracellular H⁺ to the extracellular space, preventing self-acidosis.^184–186

For photodynamic therapy (PDT) and radiation therapy (RT), oxygen plays a crucial role in the cell-killing process. The hypoxia phenomenon of TME can reduce the effectiveness of tumor treatment.^187,188 To change the hypoxic condition of tumor tissue and enhance the therapeutic efficiency of PDT and RT, researchers have investigated different strategies to overcome hypoxia. For example, liquid perfluorocarbon (PFC) can dissolve a large amount of oxygen and serve as an oxygen carrier, making it suitable as a blood substitute.^189,190 It can also be used as a catalyst for in situ oxygen production at tumor sites.^191,192 These methods can significantly improve the effectiveness of PDT. Therefore, it is essential to develop TME-sensitive intelligent therapeutic nanomaterials to regulate the TME (such as alleviating hypoxia) to improve therapeutic effects.

The nano-drug delivery system based on biomineralization can enhance the therapeutic effect on tumors by addressing tumor hypoxia. Wu and coworkers designed a biocompatible multifunctional polyelectrolyte–albumin complex and MnO₂ nanoparticles (A-MnO₂ NPs) to improve the TME by regulating hypoxia, acidosis and reactive oxygen species (ROS). On the one hand, these NPs can generate oxygen by reacting with H₂O₂ produced by cancer cells under hypoxic conditions. On the other hand, in situ generation of oxygen can alleviate hypoxia. Furthermore, this reaction can also help neutralize protons, thereby reducing acidosis. After injecting AMD NPs into the tumor, the hypoxia and acidosis of the tumor were alleviated, leading to continuous downregulation of hypoxia-inducible factors and vascular endothelial growth factors. The results showed that compared with RT alone, the combination of AMD NPs and radiation increased the killing effect on tumor cells and significantly slowed down tumor growth. This improvement may be due to manganese dioxide improving tumor hypoxia, increasing ionizing radiation, and thus enhancing the tumor inhibition effect (Fig. 8A).¹⁹³ Liu's group designed BSA biomimetic manganese dioxide nanoparticle composites.¹⁰⁷ They obtaining ¹³¹I-HSA-manganese dioxide nanomaterials by labeling the radioactive nuclide ¹³¹I. MnO₂ NPs can improve the hypoxic microenvironment of tumors and enhance the RT effect on mouse tumors. Huang's group reported a cascade catalytic reaction platform (named GMCD) for TME-specific activation. This platform alleviates tumor hypoxia by promoting oxygen self-sufficiency and improves the therapeutic effect of PDT. GMCD is constructed by co-loading catalase (CAT) and zinc porphyrin sodium (DVDMS) into manganese (Mn) doped CaP mineralized GOx nanoparticles. GMCD can effectively accumulate at the tumor site, and H₂O₂ in cancer cells can be catalyzed by CAT to generate oxygen. This not only promotes the GOx catalytic reaction to consume more intertumoral glucose but also alleviates tumor hypoxia and enhances the photo-triggered production of cytotoxic singlet oxygen by DVDMS. Moreover, the H₂O₂ generated by GOx catalysis can be converted into highly toxic hydroxyl radicals through Mn²⁺-mediated Fenton-like reactions, further amplifying the oxidative damage of cancer cells. As a result, GMCD demonstrated excellent therapeutic effects on 4T1 tumor mice by enhancing PDT through long-term cascade catalytic reactions.³⁷

Fig. 8 (A) Multifunctional A-MnO₂ NPs modulate a solid TME by attenuating hypoxia, acidosis, and vascular endothelial growth factor and enhancing the radiation response.¹⁹³ Copyright © 2014, ACS. (B) Optical images of calcified tumors; the tumor tissue became disrupted after CCTC treatment.¹⁰⁸ Copyright © 2016 WILEY-VCH. (C) μCT detection of the tumors. The left column shows a three-dimensional reconstruction and the right was a typical tomography section marked on the left.¹⁰⁸ Copyright © 2016 WILEY-VCH. (D) Evaluation of biomineral deposition on the cytomembrane surface of 143B cells after treatment with BINP at pH 7.4 or 6.5 by CLSM. The green fluorescence emitted by calcian indicates the presence of CaP (scale bar: 50 μm).⁴⁸ Copyright © 2023 Wiley-VCH. (E) Characterization of mineralized 143B cells treated with BINP at pH 7.4 or 6.5 by SEM and Ca elemental mapping (scale bar: 5 μm).⁴⁸ Copyright © 2023 Wiley-VCH.

Tumor starvation therapy is considered a potential method for treating cancer. The voracious appetite of cancer cells can consume nutrients in the blood, preventing the blood from delivering oxygen and nutrients to tumors, and consequently impeding the rapid growth of tumors.¹⁹⁴ Huang's group has developed an intelligent nano catalytic therapy diagnostic platform (called PGC-DOX) with self-sufficiency in H₂O₂ and elimination of GSH characteristics for cancer treatment. This nano platform was constructed using a one-step biomineralization method. Polyethylene glycol-modified GO was used as a template to form biodegradable copper-doped CaP nanoparticles, which were then loaded with doxorubicin (DOX). GOx can effectively catalyze the generation of H₂O₂ from intracellular glucose, not only starving tumor cells, but also providing H₂O₂ for subsequent Fenton-like reactions. At the same time, the oxidation–reduction reaction between the released Cu²⁺ and intracellular GSH will induce GSH consumption and reduce Cu²⁺ to the Fenton reagent Cu⁺. Through Cu⁺-mediated Fenton-like reactions, H₂O₂ will be triggered to produce ˙OH, thereby enhancing the efficacy of CDT. The integration of GOx-mediated starvation therapy, H₂O₂ self-sufficiency, and GSH elimination enhances CDT. Additionally, DOX-induced chemotherapy endows PGC-DOX with effective tumor growth inhibition and minimal in vivo side effects.¹¹⁸

3.2.2 Mineralization of tumor cells. Targeted mineralization of the TME is a promising cancer treatment option. Zhang's group designed an injectable polymer-modified magnesium silicate (Mg₂Si) nanoparticle. The designed nanoparticles can remove oxygen in tumors and generate by-products that inhibit tumor capillary reoxygenation, thereby acting as deoxidizers (DOA). In the acidic TME, silane is released from Mg₂Si. This released silane reacts with oxygen dissolved in the tissue and bound to hemoglobin to form SiO₂ aggregates, leading to a high consumption of oxygen within the tumor. In addition, the formation of SiO₂ through targeted mineralization in situ can block capillaries in tumors, preventing the supply of new oxygen and nutrients to the tumor site, and promoting tumor starvation therapy.¹⁹⁵ Bu and coworkers prepared calcium peroxide nanoparticles (CaO₂ NPs), which decomposed into Ca²⁺ and H₂O₂ in the acidic TME. The excessive accumulation of H₂O₂ and imbalanced Ca²⁺ transport pathways in tumor cells, Ca²⁺ overload and subsequent cell death. Meanwhile, the abundant local Ca²⁺ concentration increases the possibility of tumor calcification.¹⁹⁶

The formation of human bones and teeth is closely related to calcification and the accumulation of calcium salts.¹⁹⁷ However, calcification can also accumulate abnormally in soft tissues, triggering pathological diseases such as vascular calcification, skin necrosis, kidney stones, etc.^198,199 If a mineral coating is introduced on the cell membrane of cancer cells, it may inhibit the activity of cancer cells and lead to cancer cell death. Inspired by this, in 2016, Tang's group first proposed a drug-free cancer treatment method cell targeted mineralization (CCTC).¹⁰⁸ As is well known, folate receptors are highly expressed in many cancer cells, but are lowly expressed in normal cells.²⁰⁰ Folate receptors can specifically recognize and bind to folate. Carboxylate residues in folate can recruit and bind to Ca²⁺ in the environment, leading to an increase in local Ca²⁺ concentration and the formation of mineral layers around cancer cells, inducing cell death (Fig. 8B and C). In vivo experiments have shown that compared with conventional chemotherapy, CCTC can effectively inhibit tumor growth and metastasis without damaging normal cells. In this study, the mineralization of cancer cells required additional intertumoral injection of high concentrations of Ca²⁺. However, abnormally high levels of Ca²⁺ induced a hypercalcemia crisis. Based on this research, Tang's group designed a macromolecular drug synthesized from folic acid. This drug achieved tumor calcification for the first time using physiological concentrations of blood calcium and phosphate. Folic acid molecules can specifically bind to overexpressed folate receptors on cancer cells, while polysialic acid contains abundant carboxylic acid groups that can enrich calcium from the blood and selectively induce mineralization of tumor cells.²⁰¹In situ mineralization at the tumor site also aids in early lung cancer imaging and distinguish between cancer and benign nodules. Wang's group has designed a calcification-inducing peptide that can selectively target lung cancer cells and specifically trigger calcium precipitation on the plasma membrane of these cells without additional calcium supplementation.⁴¹

To further utilize the unique cytotoxic mechanism of Ca²⁺ and develop effective new strategies for tumor calcification, Jiang's group designed a multifunctional polymer, 1,2-distearoyl-sn-glycerol-3-phosphateethanolamine-N-(polyethylene glycol)-alendronate (DSPE-polyglycol-ALN, DPA), to induce the formation of mineral layers around osteosarcoma. After peritumoral injection, the DSPE component exhibits a chemical structure similar to that of the cell membrane, facilitating the insertion of DPA into the cell membrane. The bisphosphonic acid group of ALN is used to recruit Ca²⁺ from the environment, serving as a site for biomineralization induction to achieve biomineralization around cells. The biomineralization coating blocks the exchange of substances between tumor tissue and the external environment while inhibiting the growth and lung metastasis of primary osteosarcoma. Based on this research, the team designed and developed a biomineralization-induced nanoparticle (BINP) composed of dodecylamine polymer (γ-composed of dodecyl-L-glutamic acid)-co-(L-histidine)-block poly(L-glutamic acid graft alendronate sodium), combined with a portion for cell membrane insertion, a component responsive to TME, and an ion chelation module, and it can be used for osteosarcoma blockade therapy.⁴⁸ After intravenous injection of BINP into osteosarcoma mice, it reacts with the acidic TME, exposing dodecyl on the surface of swollen nanoparticles to promote their integration into the cell membrane. Subsequently, the extended bisphosphonic acid groups will trigger continuous ion deposition, thereby establishing a mineralization barrier around the tumor and preventing material exchange between the tumor and surrounding normal tissues (Fig. 8D and E). Zhu's group uses chondroitin sulfate as a targeting agent to induce the aggregation of exogenous Ca²⁺ and CO₃²⁻ around cancer cells, achieving in situ biomineralization of nano calcium carbonate.²² Zhang and coworkers prepared an L-type DDDEEK-pY biphenylboronic acid (SAP-pY-PBA) conjugate targeting tumors and activating biomarkers to selectively induce in situ mineralization of tumor cells. Phenylboronic acid molecules recognize polyasialic acid molecules that are overexpressed on the surface of cancer cells. DDDEEK peptides induce biomineralization, leading to cancer cell death. The overexpression of alkaline phosphatase in osteosarcoma cells breaks the phosphate group of pY, thereby triggering the self-assembly of supramolecular conjugates through hydrophobic and electrostatic interactions, forming a hydrogel coating on the cell surface. This process ultimately induces apoptosis in tumor cells.²⁰²

In addition to forming a mineral layer on the surface of the cell membrane to block the exchange of substances between tumor cells and the external environment and induce cell apoptosis, the formation of minerals inside tumor cells can interfere with organelle function and lead to the death of cancer cells. Zhang's group used PB/calcium peroxide nanocomposites as precursors. The iron mineralization generated in tumor cells significantly enhances the early and differential diagnosis of lung cancer and benign nodules through medical imaging.⁴² HPB CaO₂ (HC) increases intracellular pH and induces oxidative stress in tumor cells by generating ROS. Internalized HC can rapidly increase ˙OH concentration through the degradation of CaO₂, release Fe²⁺ or Fe³⁺, and form Fe(OH)₃ precipitates in tumor cells, leading to tumor cell iron mineralization. Excessive production of Fe²⁺ or Fe³⁺ can also catalyze H₂O₂ to generate more ROS, activate iron-mediated cell death pathways, and enhance anti-tumor efficiency. Kim's group reported a subcellular targeted biomineralization system consisting of triphenylphosphate cation (TPP) (mitochondrial-targeted portion) and trialkoxysilane (biomineralized portion through silicification). In the mitochondrial matrix (pH = 8), trialkoxysilane is hydrolyzed to produce SiO₂, which is used as an inhibitor of mitochondrial function. In addition, because TPP can target mitochondria, TPP-modified tri-alkoxysilane tends to accumulate more in cancer cells than in normal cells. In vivo evaluation confirmed that the biomineralization system effectively inhibited tumor growth in a mouse xenograft cancer model. The use of subcellular specificity and targeted strategies provides new insights into the use of intracellular biomineralization for targeted cancer treatment.¹⁰⁹ Wang and coworkers have developed an intracellular supramolecular self-assembly strategy to achieve rapid biomineralization of supramolecular peptide-encapsulated CaCO₃ in tumor cells overexpressing spermine (SPM), thereby enabling drug-free and severe side effect free treatment of tumors. FA and the peptide Phe–Val–Leu–Lys (FFVLK) are covalently coupled to PDA modified CaCO₃ nanoparticles (CaD). Subsequently, cucurbit[7]uril (CB[7]) is introduced into FFVLK through the host–guest interaction between CB and the N-terminal Phe (F) of FFVLK. Acting as a competitive inhibitor, overexpressed SPM in certain types of cancer cells can disrupt the binding pair of CB[7]-Phe (K_a ∼ 10⁵ M⁻¹), forming the CB[7]-SPM complex (K_a ∼ 10⁶ M⁻¹). Therefore, the free FFVLK will be exposed and rapidly self-assembled through hydrogen bonding, hydrophobic interactions, and π–π stacking. This layered structure triggers the self-aggregation of CaCO₃ nanoparticles. SPM-responsive CaCO₃ self-aggregation can specifically lead to overexpression of SPM in tumor cells, resulting in biomineralization, Ca²⁺ overload, severe mitochondrial damage, and apoptosis of SPM-overexpressing tumor cells.²⁰³

3.3 Hard tissue repair

Skeletal and dental injuries are the most common hard tissue damage conditions in humans. However, the current development of hard tissue repair techniques cannot meet various physiological needs. One of the most important issues is that while some repair materials exhibit good biocompatibility, they have poor interface fusion with the original bone tissue in the human body, and their mechanical strength makes it challenging to maintain consistency with the original bone tissue. The use of biomimetic mineralization strategies to treat hard tissue injuries and diseases can ensure good biocompatibility and high mechanical properties, making it an optimal approach for achieving effective tissue repair and regeneration.

3.3.1 Teeth repair. Teeth are composed of enamel, dentin, and cementum. Enamel is one of the hardest biological materials in living organisms, a highly mineralized biological tissue with apatite crystals making up over 96% of its composition. Although enamel formation (enamel formation) is a part of the entire process of biological development, mature enamel is cell-less and rarely self-repairs after injury.²⁰⁴ Therefore, dental caries or cavities are one of the most common chronic diseases among humans worldwide.²⁰⁵ Researchers have made great attempts in enamel remineralization, including strategies such as direct solution mineralization,^206,207 protein/peptide-induced mineralization,^208–210 hydrogel-driven mineralization^211–213 and precursor assembly.^214–216

Casein phosphopeptide (CPP) containing phosphate residues binds to calcium and phosphate ions to prevent ACP from transforming into HAP crystals, thereby forming amorphous nanocomposites CPP–ACP in metastable solutions.²¹⁷ CPP–ACP serves as a supersaturated calcium and phosphate reservoir on the surface of enamel, promoting mineralization of enamel surface damage.²¹⁸ Amelogenin can stabilize ACP and alter aggregation, producing directional rod-shaped HAP crystals.^219,220 Kim's group reported that when amelogenin was added to a fluoride-containing mineralizing medium, it could promote the formation of a well-organized enamel-like structure,²²⁰ and also developed a chitosan hydrogel containing amelogenin for enamel regeneration, which facilitated the assembly of enamel-like layers on mature enamel. Amelogenin contains abundant tyrosine and phosphate-modified self-assembled peptide sequences, which may play a key role in mediating tooth remineralization. Inspired by this, Chen's group developed a novel biocompatible peptide scaffold (named LCPS-OP and LCPS-CP, respectively) based on a flexible self-assembled low-complexity protein fragment (LCPS) containing phosphate or phosphonate groups.²²¹ Research has shown that coating LCPS-OP and LCPS-CP on the surface of corroded enamel promotes the epitaxial growth of hydroxyapatite, generating restorative enamel equivalent to natural enamel and reducing the adhesion of Streptococcus mutans (Fig. 9A and B).²²¹

Fig. 9 (A) CLSM images of S. mutans biofilm distribution on the different enamels (without biofilm or with biofilm plus enamel coating with No Peptide, LCPS-OH, LCPS-OP, or LCPS-CP). Scale bar: 100 μm.²²¹ Copyright © 2022 Wiley-VCH. (B) Matrix mineralization of MC3T3-E1 cells treated with LCPSs; scale bar: 200 μm.²²¹ Copyright © 2022 Wiley-VCH. (C) SEM image showing both acid-etched enamel and repaired enamel.²²² Copyright © 2019 AAAS. (D) A three-dimensional AFM image of repaired enamel.²²² Copyright © 2019 AAAS. (E) High-magnification SEM image of the red circle in (C).²²² Copyright © 2019 AAAS. (F) Designer dual therapy nanolayered implant coatings eradicate biofilms and accelerate bone tissue repair.²²³ Copyright © 2016 ACS.

Biomineralization occurs at a complete crystalline-amorphous interface, where the crystalline mineral phase is covered by its amorphous precursor to maintain a continuous epitaxial structure. Inspired by this, Shao group's research found that CaP ion clusters (CPICs) can facilitate enamel remineralization.²²² These CPICs can generate a precursor layer on the surface of enamel, thereby inducing the epitaxial crystal growth of enamel apatite.  The unique feature of natural enamel could be precisely replicated within 48 hours by using the CPICs material. Importantly, the repaired enamel exhibits the same morphological texture as natural enamel, with well-arranged enamel rods (Fig. 9C–E).²²²

3.3.2 Bone repair. Bone is a graded hard tissue with a graded structure, consisting of hydroxyapatite-oriented crystals embedded in type I collagen fibers.²⁰⁴ Currently, bone defects and osteoporosis are the two main areas of research in bone repair. Osteoporosis is a systemic bone disease characterized by decreased bone density and quality, destruction of bone microstructure, and increased bone fragility due to various factors (such as malnutrition, protein deficiency, etc.), making bones more susceptible to fracture. It is a chronic disease that cannot be cured, characterized by a lack of minerals such as hydroxyapatite in the bones. Currently, clinical treatment of osteoporosis mainly relies on drugs, including vitamin D,²²⁴ bisphosphonates,^225,226 and calcium supplements.²²⁷ However, these treatments cannot restore the healthy state of osteoporotic bones.²²⁸ Inspired by biomineralization, Yao's group prepared a free-flowing CaP polymer-induced liquid precursor (CaP PILP), composed of two negatively charged polymers (PAA and PASP).¹⁰⁵ PAA has a high molecular weight and is used to stabilize the PILP phase of CaP. PASP, as a competitor of PAA, binds to Ca²⁺ and thus prevents PAA from precipitating at high Ca²⁺ concentrations. Research has shown that this free-flowing CaP PILP can easily penetrate collagen fibers and form intra-fiber hydroxyapatite crystals oriented along the c-axis. In vitro experiments have shown that CaP-PILP has a strong affinity for osteoporotic bone and can distribute evenly throughout bone tissue, significantly increasing bone density.¹⁰⁵In vivo experiments have shown that CaP PILP restores the density, Young's modulus, and hardness of osteoporotic bone similar to natural bone after 8 weeks of treatment, indicating that CaP-PILP can quickly and effectively repair osteoporotic bone.¹⁰⁵

So far, autologous bone transplantation has been considered the “gold standard” for bone replacement, but its availability and potential compatibility issues are limited.^229,230 An ideal bone substitute material should have advantages such as good bone conductivity, biocompatibility, absorbability, and sufficient mechanical strength.²³¹ Therefore, many bone substitute materials, such as metal materials, ceramic implants, polymer scaffold materials, and hydrogels, have been used for bone regeneration.²³² Gong and coworkers have developed a new type of double network hydrogel that can spontaneously and safely bond with defective bone in vivo. The high degree of osseointegration of hydrogels is achieved by mineralizing CaPHAP nanospheres in the surface layer of hydrogels to induce spontaneous osteogenesis and infiltration into semipermeable hydrogels. This was the first successful integration of hydrogel and bone.²³³ Using LbL technology, Min's group has prepared an injectable dual-therapeutic nano-layer implant coating that can effectively and rapidly repair bone tissue.²²³ LbL technology enables the continuous formation of antibiotics (gentamicin) and bone-inducing growth factor (BMP-2) on the coating surface. This hydrolyzable and degradable multilayer film can eliminate the established biofilm in rats with induced osteomyelitis and enable rapid repair of bone tissue around the implant (Fig. 9F).²²³ P. K. M.'s group reported on the production of a biomineralized recombinant peptide scaffold that enhances the expression of osteocalcin. Using simulated nucleation to produce linear mineralized scaffolds, they improved the mechanical strength, increased HA content, and enhanced osteoblast mineralization. All three scaffold signals, mechanical, chemical, and material structures, are optimized together, which is important and necessary for guiding cellular responses in bone regeneration engineering.²³⁴ Based on this, L. Y. 's group reported an elastic bioactive nanocomposite material with multifunctionality in biomineralization activity, elastic behavior, biological imaging tracking, osteoblast response, and inflammatory response.²³⁵ It has been proven that external electrical stimulation can be used to improve bone regeneration and promote bone healing.²³⁶ However, it is still unclear how to control electrical stimulation to adapt to physiological potentials. Z. C. G.'s group has proposed a new method for controlling the surface potential of periosteum to enhance and optimize regenerated bone tissue. Polyvinylidene fluoride (PVDF-TRFE) is a flexible and stable bone healing material that is used as a template to study the relationship between osteogenic outcomes and surface potential. Research has shown that bone healing materials with the appropriate surface potential can serve as a periosteal substitute in bone engineering.²³⁷

3.4 Bioimaging

Biosensors and imaging technologies are used in disease monitoring. The application of these technologies in clinical medical diagnosis is becoming increasingly important. To date, many sensors and contrast agents have been developed that utilize bioluminescence, fluorescence, photoacoustic effects, photothermal effects, and so on. In these strategies, inorganic nanomaterials such as carbon nanotubes, metals, and metal oxide nanoparticles are used for labeling and tagging biomolecules to create inorganic nanomaterial–biomolecule hybrids. These hybrids have similar functions to biomolecules, better biocompatibility, and more precise targeting.

Xie and colleagues prepared biomineralized nanoparticles (OA@MnCaCs) by encapsulating oncolytic adenoviruses (OA) with calcium carbonate and manganese mineral shells (MnCaCs) (Fig. 10A). The shell has the function of invisibility to the immune system and prolongs internal circulation. In addition, the mineral shell rapidly dissolves in the acidic microenvironment of tumor cells and releases oxidative Mn²⁺, promoting the endogenous conversion of H₂O₂ to oxygen. The coexistence of Mn²⁺ and oxygen enhances the signals displayed in magnetic resonance imaging (MRI) and photoacoustic imaging (PAI), enabling dual-mode imaging and cancer treatment.²³⁸

Fig. 10 (A) Schematic illustration of the preparation of OA@MnCaCs nanoparticles and their application in dual-modality imaging-guided and synergistically enhanced anticancer therapy.²³⁸ Copyright © 2019 ACS. (B) Rapid and multimodal in vivo bioimaging of cancer cells through in situ biosynthesis of Zn&Fe nanoclusters.²³⁹ Copyright © 2017 Tsinghua University Press.

On the other hand, inorganic minerals formed in situ can also serve as imaging reagents in the absence of virus invasion into cells.^240,241 Wang and coworkers reported a multimodal in vivo biogenesis strategy for in situ biosynthesis of zinc and iron nanoclusters in cancer cells (i.e. HeLa, U87, and HepG2 cancer cells) (Fig. 10B). By introducing aqueous Fe²⁺ and Zn²⁺ solutions into the cancer cells, they form magnetic Fe₃O₄ nanoclusters and fluorescent ZnO nanoclusters in the cells. By combining fluorescence imaging with magnetic resonance imaging and computed tomography, these clusters can be used for multimodal cancer imaging. No fluorescence or other significant differences were detected in normal cells (i.e. L02) and tissues before and after injection.²³⁹ Fan and coworkers prepared a tumor-activated Fe@HRP-ABTS/GOx nanodot, which activates glucose-responsive tumor therapy and increases H₂O₂ concentration at the tumor site by oxidizing glucose in tumor cells. More importantly, H₂O₂ can be catalyzed by horseradish peroxidase (HRP) to convert ABTS (2,2′-hydrazine-bis(3-ethylbenzothiazoline-6-sulfonic acid) diamine salt) to oxidized ABTS (oxABTS) for PTT and photoacoustic (PA) imaging.²⁴²

4. Perspectives

At present, researchers have made great progress in developing biohybrid materials based on the concept of biomimetic mineralization. However, there are still many challenges and opportunities to be faced in future research.

Firstly, how can we further enrich the types of biohybrid materials? Tang's group proposed a new material, namely inorganic ion oligomers, which can be used to create mineralized continuous materials through inorganic ion polymerization reactions, bridging the gap between inorganic chemistry and polymer chemistry.²⁴³ This innovative concept of materials and reactions will undoubtedly contribute to the diverse design and industrial preparation of biomimetic mineralization engineering materials.

Secondly, how can we further enrich the functions of biohybrid materials? In the process of evolution, precise biomineralization structures can enable organisms to acquire special functions such as photosensitivity, magnetotaxis, and protection. However, the current biohybrid materials cannot yet achieve precise biomineralization structures, and therefore cannot achieve the same functional effects as natural life forms. This will also become a goal for researchers to continue exploring.

In addition, how can the obtained biohybrid materials be more widely applied in the biomedical field? At present, attempts have been made to apply biohybrid materials in vaccine storage, active component protection, biological stealth, and drug delivery. However, most of these applications are still in the basic theoretical research stage. Achieving clinical medical transformation still requires more investment in scientific research.

Furthermore, how can we create new functional life forms? Many organisms do not possess the ability for spontaneous biomineralization. Researchers have introduced inorganic structures into these organisms through biomimetic mineralization methods. By integrating and functionally regulating materials and organisms, they can generate “new functional life forms.” This will provide technical support for promoting biological evolution, which may involve the needs of future space exploration and serve as an important scientific basis for the transformation from a carbon-based civilization to a silicon-based civilization.

Finally, it should be noted that biomimetic mineralization technology can integrate biological organisms with inorganic nanofunctional materials to create a wider range of biohybrid materials, but there are also inherent risks. The use of biomimetic mineralization technology can be utilized to protect life-saving vaccines and to combat deadly viruses that pose a widespread threat. Therefore, it is necessary to establish rules for research in this field from the perspectives of medical ethics and law. Only in this way can biomimetic mineralization technology better serve the advancement of human civilization.

Biomimetic mineralization, as a preparation strategy for advanced biomaterials, can enable humans to achieve organic regulation through biohybrid materials to better adapt to the environment. This process can further generate an evolutionary chain that is more conducive to their own development. By learning from nature, research on biomimetic mineralization based on nanotechnology will provide new directions for the sustainable development of humanity.

Author contributions

This manuscript was written through contributions from all authors. All authors have given approval to the final version of the manuscript.

Data availability

Data availability is not applicable to this article as no new data were created or analyzed in this study.

Conflicts of interest

There are no conflicts of interests to declare.

Acknowledgements

The work was supported by the National Natural Science Foundation of China (no. 22175096, 22275095), the Jiangsu Key Laboratory of Biofunctional Materials, the Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, and the Qinglan Project Foundation of Colleges and Universities of Jiangsu Province.

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