Progress in the Applications of Polymer-Decorated Black Phosphorus and Black Phosphorus Analog Nanomaterials in Biomedicine

Aoqi Su; Xinyu Li; Ran Wang; Lili Gao; Tifeng Jiao

doi:10.7536/PC240417

2025 , Vol. 37 >Issue 2: 133 - 156

Review

Progress in the Applications of Polymer-Decorated Black Phosphorus and Black Phosphorus Analog Nanomaterials in Biomedicine

Aoqi Su ,
Xinyu Li ,
Ran Wang ,
Lili Gao ,
Tifeng Jiao ^,^*

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Hebei Key Laboratory of Applied Chemistry, School of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004, China

^* e-mail: tfjiao@ysu.edu.cn

Received date: 2024-05-08

Revised date: 2024-09-09

Online published: 2025-02-07

Supported by

National Natural Science Foundation of China(22072127)

National Natural Science Foundation of China(22372143)

Hebei Natural Science Foundation(C2018203374)

Hebei Natural Science Foundation(B2021203016)

Hebei Natural Science Foundation(B2023203018)

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Abstract

In the realm of two-dimensional nanomaterials, black phosphorus (BP) is considered a promising candidate to address the shortcomings of graphene and transition metal dichalcogenides (TMDs). Low- dimensional black phosphorus (BP) refers to a class of nanomaterials derived from the layered semiconductor BP. These materials exhibit high structural anisotropy, tunable bandgap widths, and high hole and electron mobility, endowing BP with unique properties such as conductivity, photothermal, photodynamic, and mechanical behaviors. BP's near-infrared light response significantly enhances its effectiveness in photothermal and photodynamic antibacterial applications. Additionally, due to its unique layered structure, BP nanosheets (BPNS) possess a high surface-to-volume ratio, making them excellent carriers for loading and delivering other antimicrobial nanomaterials or drugs. First, this article discusses the physical properties of low-dimensional BP and introduces various preparation methods. Furthermore, it systematically reviews exciting therapeutic applications of polymer-modified black phosphorus nanomaterials in various fields, such as cancer treatment (phototherapy, drug delivery, and synergistic immunotherapy), bone regeneration, and neurogenesis. Finally, the paper discusses some challenges facing future clinical trials and potential directions for further research.

Contents

1 Introduction

2 Preparation methods of BPNs

2.1 Mechanical exfoliation

2.2 Ultrasonication-assisted liquid exfoliation

2.3 Electrochemical exfoliation

2.4 Chemical vapor deposition (CVD)

2.5 Hydro/solvothermal synthesis

3 Structure and properties of BPNs

3.1 Structure of BPNs

3.2 Properties of BPNs

4 Biomedical application

4.1 Disease diagnosis

4.2 Therapeutic strategies

5 Conclusion and outlook

Key words： low-dimensional black phosphorus; bioimaging; physical properties; biomedical applications

Cite this article

Aoqi Su , Xinyu Li , Ran Wang , Lili Gao , Tifeng Jiao . Progress in the Applications of Polymer-Decorated Black Phosphorus and Black Phosphorus Analog Nanomaterials in Biomedicine[J]. Progress in Chemistry, 2025 , 37(2) : 133 -156 . DOI: 10.7536/PC240417

1 Introduction

Black phosphorus (BP) is a two-dimensional (2D) semiconductor material^[1], and a strong successor to other 2D nanomaterials such as graphene, transition metal dichalcogenides (TMDs), hexagonal boron nitride (hBN), metal carbides and nitrides (MXenes), primarily due to its inherent atomic structure and versatile physical properties. Due to the inequivalent sp³ hybridization orbitals of phosphorus atoms in black phosphorus, a puckered honeycomb structure extending along the armchair (AM) direction is formed, which exhibits significant in-plane anisotropy for photogenerated carriers and thermal conductivity. Moreover, compared with graphene and other analogues, this puckered structure provides a larger specific surface area. Interestingly, unlike gapless graphene and TMDs with indirect bandgaps, BP exhibits a tunable direct bandgap of 0.3~2 eV, which mainly depends on its layered structure. In addition, BP also possesses many other properties, such as excellent photoresponse and high carrier mobility (approximately 1000 cm²/(V·s)), making it widely applicable in electronics, optoelectronics, energy storage, electrocatalysis, sensors, and biomedicine. The element P plays a crucial role in the human body and is a component of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and adenosine triphosphate (ATP). As the most stable allotrope of the element P, BP is considered a reliable biomaterial. Furthermore, its well-known light absorption capability, optical response in the near-infrared (NIR) region, photovoltaic effect, photothermal effect, and physical characteristics related to specific surface area make it a potential candidate nanoformulation capable of overcoming biomedical challenges.

Based on material granularity and structural components, low-dimensional BP materials are divided into BP nanosheets (BPNS), BP quantum dots (BPQDs), and heterogeneous BP mixtures (including heterostructures and non-heterostructures). Notably, the crumpled honeycomb lattice structure endows low-dimensional BP with strong anisotropy, further bringing significant physical advantages. For instance, when phonon scattering occurs on the surface of BP, various Raman signals reflected along the AM direction are more numerous than those in the zigzag (ZZ) direction. Moreover, the bandgap gradually increases as the number of layers decreases. This tunable bandgap usually affects the light absorption capability of low-dimensional BP. Such a characteristic is highly suitable for biomedical research, such as cancer photothermal therapy (PTT), photodynamic therapy (PDT), and X-ray-induced photodynamic therapy.

To expand the biomedical applications of low-dimensional BP, researchers have explored various BP preparation methods, such as liquid-phase exfoliation, electrochemical-assisted delamination, and solvothermal methods. Additionally, when BP is modified with different functional polymers, it exhibits strong physiological stability and enhanced biological effects. Other materials, such as graphene, graphitic carbon nitride (g-C₃N₄), and Au nanoparticles, can also be integrated with BP to form heterogeneous BP hybrids with rich physicochemical properties. Moreover, modification strategies such as chemical treatment, non-covalent surface modification, and encapsulation play a crucial role in broadening the application prospects of BP.

This paper discusses the physical properties of low-dimensional BP and introduces various preparation methods, providing a systematic summary of the progress in the application of polymer-modified black phosphorus nanomaterials in the biomedical field, such as cancer treatment (phototherapy, drug delivery, and synergistic immunotherapy), bone regeneration, and neurogenesis. Finally, it discusses some of the challenges faced in future clinical trials and possible directions for further research.

2 Preparation Method of BPNs

Compared with bulk BP, BPNs (single-layer or few-layer BP) possess a higher specific surface area and reactivity due to their unique two-dimensional folded honeycomb structure. Currently, there are two strategies for preparing biological BPNs: top-down exfoliation and bottom-up synthesis. The top-down exfoliation method involves the disruption of interlayer interactions to peel bulk BP into BPNs through mechanical exfoliation, ultrasonic-assisted liquid exfoliation, and ion/molecular intercalation (e.g., electrochemical exfoliation). On the other hand, BPNs can be obtained using bottom-up synthesis methods by vapor-phase evaporation assembly of precursors such as WP and RP for synthesis or vacuum evaporation synthesis (e.g., hydrothermal/solvothermal synthesis).

2.1 Mechanical Exfoliation

In 2014, BPNs were first prepared by using transparent tape to mechanically exfoliate bulk BP^[2]. The isolated nanosheets were transferred onto a silicon (Si) substrate, and organic solvents including acetone, isopropanol, and methanol were used to remove the residual adhesive from the tape. BPNs were obtained after heating at 180 ℃ to remove the remaining solvent. Using this method, Li et al.^[2] discovered that monolayer BPN (thickness of 0.85 nm) exhibited a photoluminescence (PL) signal with a width of 100 meV at 1.45 eV, while bulk BP did not show any PL signal^[2]. However, this method has drawbacks such as low yield, difficulty in controlling the size, shape, and thickness of the produced BPNs, and the cumbersome process of removing the sticky adhesive from the surface of the BPNs. To improve the exfoliation efficiency, Lu et al.^[3] combined mechanical cutting with plasma etching techniques. First, few-layer BPNs were prepared on a Si substrate through mechanical exfoliation; then, single-layer BPNs were produced using an Ar⁺ plasma thinning process. In another study, Guan et al.^[4] deposited a layer of gold or silver on a Si substrate to enhance the adhesion between BPNs and the substrate (Figure 1). The morphology and crystal structure of the BPNs prepared by this metal-assisted mechanical exfoliation were well preserved. Moreover, the exfoliation yield of this method was 100 times higher than that of the transparent tape method. Generally, BPNs can be simply prepared by mechanical exfoliation, but the low yield and random thickness and size limit their widespread application.

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图1 BPN的金属辅助机械剥离^[4]

Fig. 1 Metal-assisted mechanical exfoliation of BPNs^[4]

2.2 Ultrasonic-Assisted Liquid Exfoliation Technique

The ultrasonic-assisted liquid exfoliation method has become a general technique for preparing 2D nanomaterials (such as graphene, MoS₂, and WS₂). This method has also shown promise in the preparation of BPNs^[5]. In this method, bulk BP is dispersed in a suitable solvent and exfoliated using ultrasonic treatment. High-amplitude ultrasound provides shear forces and cavitation, leading to the separation of BP layers^[6]. In Kang et al.'s recent work^[7], the exfoliation efficiency of BPNs was improved by using an ultrasonic homogenizer with higher ultrasonic power than conventional bath-type ultrasonic cleaning devices (Figures 2A and B). As the centrifugation rate increased, the color of the harvested BPNs suspension changed from brown to light yellow (Figure 2C), indicating that at higher centrifugal speeds, the BPNs had smaller size, fewer layers, and lower concentration.

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图2 超声波辅助液相剥离BPNs的研究：(A)常规超声波清洗槽的BPNs的剥离过程^[7]；(B)超声波粉碎机的BPNs的剥离过程^[7]； (C) 以不同速度离心后获得的NMP中BPNs混悬液的照片^[7] (1)制备时；(2)500 r/min；(3)5000 r/min；(4)10 000 r/min；(5)15 000 r/min）；(D)不同溶液中剥离的BPNs的照片；(E)在不同溶剂中超声处理BP（1 mg/mL）3 h，然后以3000 r/min离心30 min后，剥离的BPNs的浓度^[11]

Fig. 2 Ultrasonication-assisted liquid exfoliation of BPNs：(A) Exfoliation process of BPNs using conventional ultrasonic cleaning bath^[7], (B) Exfoliation process of BPNs using ultrasonic disintegrator^[7], (C) Photograph of the BPN suspension in NMP obtained after centrifugation at different speeds ((1) As prepared; (2) 500 r/min; (3) 5000 r/min; (4) 10 000 r/min; (5) 15 000 r/min)^[7], (D) Photos of stripped BPNs in different solutions, (E) Concentration of exfoliated BPNs after ultrasonication of BP (1 mg/mL) in different solvents for 3 h followed by centrifugation at 3000 r/min for 30 min^[11]

The choice of solvent is crucial for ultrasonic-assisted liquid exfoliation as it significantly affects the exfoliation efficiency. The surface energy of the solvent should be similar to that of BP (35~40 mJ/m²)^[8] to effectively weaken the van der Waals forces between BP layers, thereby promoting exfoliation and avoiding the re-aggregation or sedimentation of the exfoliated nanosheets, which is beneficial for the dispersion of two-dimensional materials. Brent et al.^[9] used N-methylpyrrolidone (NMP) as a solvent to prepare BPNs with sizes up to 200 nm×200 nm by sonicating at 820 W for 24 hours. The surface energy of NMP (40 mJ/m²) closely matches that of BP. Yuan et al.^[10] found that BPNs exhibited higher stability and thickness controllability in alkaline NMP solvent than in NMP, achieving higher BPN yields (Fig. 2D)^[10], possibly because the zeta potential of BPNs in alkaline NMP (-30.9 mV) was higher than that in NMP (-19.7 mV), significantly enhancing their stability. Apart from NMP, other organic solvents such as dimethyl sulfoxide (DMSO), levulinic acid (LA), propylene carbonate (PC), isopropanol (IPA), 1,3-dimethyl-2-imidazolidinone (DMI), N-cyclohexyl-2-pyrrolidone (CHP), and dimethylpropylene urea (DMPU) were also attempted for the exfoliation of bulk BP. It was found that the solvent DMPU had the highest efficiency (Fig. 2E)^[11]. Although aprotic polar solvents are beneficial for liquid-phase exfoliation, these organic solvents are generally not suitable for biomedical applications due to toxicity^[12]. Water is a non-toxic option, but its surface tension (72 mJ/m²)^[13] is much higher than that of BP. Biomacromolecules, surfactants, and some polymers have been used to reduce the surface tension of water and stabilize the exfoliated BPNs^[12], but the results remain unsatisfactory. Therefore, it is still necessary to find a non-toxic solvent for efficient exfoliation of BPNs while ensuring that the prepared BPNs possess high stability.

2.3 Electrochemical Exfoliation

Although the ultrasonic-assisted liquid-phase exfoliation method for BPNs is simple and effective, it is time-consuming and has a low yield. To overcome the above issues, another top-down exfoliation method called electrochemical exfoliation has been developed^[14-15]. This method uses aqueous solutions of Na₂SO₄ or H₂SO₄^[16], PC solutions of alkylammonium salts such as tetrabutylammonium bisulfate (TBA·HSO₄)^[17], aqueous solutions of cetyltrimethylammonium chloride (CTAC)^[18], and DMSO solutions of tetrabutylammonium tetrafluoroborate (TAAB)^[19] as electrolytes for BP electrochemical exfoliation. In electrochemical exfoliation, an external electric field is used to drive ions from the electrolyte into the interlayers of bulk BP, weakening the van der Waals forces between the BP layers. Additionally, the electric field induces the reduction of protons, oxidation of hydroxide ions, or decomposition of inserted ions, generating bubbles that ultimately delaminate BP^[20]. Depending on the position of BP in the exfoliation system, the electrochemical exfoliation of BP can be classified into anodic exfoliation, cathodic exfoliation, and electrolyte exfoliation.

Compared with ultrasonic-assisted liquid-phase exfoliation, electrochemical exfoliation for producing BPNs offers higher yield, better crystal quality, and higher carrier mobility. However, the obtained BPNs have a relatively larger thickness, which implies a narrower bandgap, lower photothermal conversion efficiency, and poorer stability, making them less suitable for photothermal antibacterial applications.

2.4 Chemical Vapor Deposition (CVD)

CVD is a technique used for preparing solid films through chemical reactions of vapor precursors adsorbed on the substrate surface. The CVD process includes three key steps: the formation of vapor precursors, the transfer of vapor precursors to the substrate, and the subsequent formation of thin films on the substrate through chemical reactions. CVD is a typical bottom-up method for preparing BPNs, where vaporized BP or BP precursors are loaded onto the surface of a specific substrate to generate BPNs. In 2015, Hu et al^[21] first applied CVD to prepare BPNs. As shown in Figure 3, RP was used as a precursor, thermally deposited on a flexible polyethylene terephthalate (PET) substrate at 400 ℃ for 10 minutes, and then the RP film was converted into a BP film under high pressure (8 GPa). The obtained BP film (tens of layers of BPNs) had a diameter of 4 mm and a thickness of 40 nm, which was thicker than films prepared by top-down methods. Additionally, using PET as a substrate led to impurity defects in the BP film due to the reaction between the phosphorus precursor and the PET substrate during the CVD process. Consequently, the crystal quality and hole mobility (0.5 cm²/(V·s)) of the BP film were relatively low. To address these issues, Shriber et al. selected sapphire instead of PET as the substrate because sapphire exhibits high stability and inherent inertness towards phosphorus even at high temperatures and pressures^[22]. This approach improved the crystal quality of the BP film and its hole mobility (up to 160 cm²/(V·s)).

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图3 通过CVD从RP粉末合成薄BP膜的装置^[21]

Fig. 3 Apparatus for synthesizing thin BP films from RP powder via CVD^[21]

To date, only a few studies have reported the successful fabrication of BPNs through the CVD method. Compared with mechanical exfoliation and ultrasonic-assisted liquid-phase exfoliation, the CVD method can obtain BPNs with larger lateral dimensions and uniform thickness. However, the reaction conditions required for the CVD method are harsh and dangerous, such as high temperature and high pressure. Additionally, the fabricated BPNs are usually relatively thick and have low crystal quality. Therefore, the substrate materials, phosphorus precursors, and CVD reaction conditions should be optimized to improve the quality of the prepared BPNs.

2.5 Hydrothermal/Solvothermal Synthesis

In addition to CVD, solvothermal synthesis is another bottom-up strategy for preparing BPNs (Figure 4A). For instance, Zhang et al.^[23] successfully synthesized BPNs with a lateral size of 1 μm and a thickness of 0.5~4 nm (1~8 layers) in 2016 (Figure 4B). This solvothermal reaction used RP particles as precursors and ethanol as the solvent, reacting at 400 ℃ for 24 hours. Furthermore, Chen et al.^[127] achieved higher efficiency (approximately 2 layers) in hydrothermal synthesis of BPNs. The reaction was carried out under milder conditions (200 ℃, 16 hours), where the surface activation energy of RP was reduced by adding ammonium fluoride (NH₄F) to the reaction system (Figure 4C). Tian et al.^[24] used the solvothermal method to synthesize BPNs at a lower temperature using WP as the FAB reactant. Ethylenediamine (EDA) can easily dissolve WP and dissipate heat to promote the thermal transformation of WP to RP and ultimately to BPNs (Figure 4D), so EDA was chosen as the solvent. Ozawa et al.^[25] used RP instead of WP as the precursor for synthesizing BPNs in EDA and found that the reaction efficiency was improved. Additionally, they discovered that the reaction temperature, particle size, and initial concentration of RP significantly affect the yield of BPNs. Since there is no need to pre-prepare dispersed BP, the hydrothermal/solvothermal method enables large-scale production of BPNs and reduces production costs. Compared with top-down exfoliation methods, the hydrothermal/solvothermal synthesis process is simpler, but the crystallinity of the prepared BPNs is relatively poor, which limits their applications in optics, electronics, and biomedicine.

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图4 (A)使用溶剂热法合成BPN的程序^[23]；(B)AFM；(C)SEM；(D)TEM

Fig. 4 (A) Synthesis procedure of BPNs using a solvothermal method^[23]; (B)AFM; (C)SEM; (D)TEM

3 Structure and Properties of BPNs

3.1 Structure of BPNs

Unlike the 2D honeycomb lattice structure of graphene, BPNs exhibit a folded honeycomb structure generated by sp³ orbital hybridization. As shown in Figure 5, in-plane and out-of-plane P atoms are connected by strong P—P σ bonds with bond lengths of 2.224 Å (1 Å = 0.1 nm) and 2.244 Å, respectively. The interlayer interactions in BPNs are governed by van der Waals forces, with an interlayer spacing of 5.3 Å^[26-27]. BPNs display armchair patterns at different angles along the x-axis and y-axis^[28], with bond angles of 96.3° and 102.1°, respectively. Each P atom in BPNs is covalently bonded to three neighboring P atoms through strong single bonds, which endows BPNs with high carrier mobility and bipolar transport characteristics^[29]. Meanwhile, lone electron pairs on the triply coordinated P atoms result in unusual chemical and biological activity of BPNs^[30].

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图5 BPNs的原子球杆模型:（A）3D表示；（B）顶视图；（C）侧视图^[26]

Fig. 5 Atomic ball-and-stick model of BPNs: (A) 3D representation; (B) top view; (C) side view^[26]

3.2 Properties of BPNs

Compared with WP and RP, BP exhibits higher thermodynamic stability and does not spontaneously ignite when heated to 400 ℃ in air^[31]. BP is the most stable allotrope of phosphorus and possesses excellent biocompatibility^[32]. Refining BP into BPNs can widen the bandgap from 0.3 eV to 2.0 eV^[33], thereby generating customizable optical, electrical, mechanical, and thermal properties. Additionally, the unique folded honeycomb 2D structure endows BPNs with distinctive anisotropic characteristics, making them an attractive research topic.

3.2.1 Direct and Tunable Bandgap

As shown in Fig. 6A, graphene and MoS₂ (the most widely reported 2D materials) have zero bandgap and large bandgap (1.5~2.5 eV), respectively ^[34]. In contrast, the bandgap of BP varies from 0.3 eV to 2.0 eV, which fills the gap between graphene and MoS₂ and allows a wide range of absorption across the visible and NIR regions. This makes BP have better application prospects in the fields of photodynamic and photothermal antibacterial applications ^[35]. In 1953, Kumer et al. ^[36] measured the bandgap of bulk BP to be 0.33 eV through conductivity experiments. In 2014, Tran et al. ^[37] demonstrated that BP is a semiconductor with a direct bandgap via the GW-Bethe-Salpeter equation, and the simulation results showed that the bandgap range of BP is from 0.3 eV for bulk to 2.0 eV for monolayer. In 2016, Li et al. ^[38] measured the bandgaps of monolayer, bilayer, and trilayer BPNs as well as bulk BP to be 1.73, 1.11, 0.83, and 0.35 eV, respectively. This confirmed that BP has a strong layer-dependent electronic structure. By measuring the PL spectrum, they further found that the PL peak energy of BP highly coincides with the absorption energy in the absorption spectrum, proving the directness of the BP bandgap experimentally for the first time. However, due to the differences in calculation methods and the imprecise measurement of sample thickness, the bandgap value of BP varies in different studies. Nevertheless, these studies all indicate that the bandgap of BP decreases as the number of layers increases. This is because BP has a folded honeycomb structure, and its electronic states are sensitive to external influences ^[39]. The increase in the number of layers leads to band splitting in the Brillouin zone, resulting in a reduced bandgap ^[40].

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图6 (A)典型二维材料的电磁波谱和带隙范围^[34]； (B)BPNs在降解过程中释放出对细胞无毒的PO₄^3-和PO₃^3-^[43]；(C) BPNs的光诱导环境降解过程^[46]

Fig. 6 (A) Electromagnetic wave spectrum and bandgap ranges of typical 2D materials^[34]；(B) BPNs release PO₄^3-and PO₃^3-during degradation, which are non-toxic toward cells^[43]；(C) The light-induced ambient degradation process of BPNs^[46]

3.2.2 Electrical Conductivity

Keyes^[41] proposed a new method in 1953 to study the electrical properties of BP under different pressures and temperatures. The research showed that the hole and electron mobility of BP as functions of temperature are 1.9×10⁶T^-3/2cm²/(V·s) and 1.2×10⁶T^-3/2cm²/(V·s), respectively, indicating that the mobility decreases with increasing temperature^[41]. Additionally, Tang et al.^[42] found that the carrier mobility of BPNs is thickness-dependent. They observed that the hole mobility of BPNs with a thickness of 10 nm is 1000 cm²/(V·s), while for BPNs with a thickness of 15 nm, the hole mobility is only 650 cm²/(V·s)^[42].

3.2.3 Biocompatibility

BP consists of phosphorus, an essential element for the human body, accounting for approximately 1% of body mass. Its degradation products PO₄^3- and PO₃^3- are non-toxic to human cells (Figure 6B). Sun et al.^[43] used the 5-diphenyl-2-tetrazolium bromide assay to evaluate the cytotoxicity of BPNs on human cervical cancer cells (HeLa), and the results showed that cell viability remained high even when the BPNs concentration reached 1280 μg/mL. Shao et al.^[44] also found that BPNs exhibited no cytotoxicity towards L929, human mesenchymal stem cells, human breast cancer cells, and HeLa cells. Moreover, after injecting BPNs into healthy mice for 20 days, no significant histological abnormalities or lesions were observed in major organs such as the liver, spleen, kidney, heart, and lungs. Notably, when BPNs come into contact with blood, they are immediately covered by plasma proteins. These proteins influence the interaction between BPNs and cells and further improve the cytocompatibility of BPNs^[45]. These results indicate that BPNs possess excellent biocompatibility, making them highly promising for biomedical applications. Since BPNs are derived from inorganic phosphorus, which is widely present in nature, their application does not raise ethical concerns.

3.2.4 Instability

BPNs have been extensively studied due to their unique bandgap and electronic properties. However, their high reactivity and susceptibility to degradation in air and water limit their potential applications. For instance, Zhou et al^[46] reported in 2016 that when BPNs are exposed to air and water, they undergo oxidation and gradually degrade into PO₄^3- and PO₃^3- (Figure 6C) due to the reactivity of lone pair electrons and an ultra-large specific surface area. Subsequently, under light conditions, O^2- is generated on the surface of BPNs (Step I), followed by O^2- being adsorbed by P atoms to form a P_xO_y oxide layer (Step II). This oxide layer protects the BPNs and slows down the degradation rate but can further react with H₂O to form phosphoric acid, leading to the cleavage and decomposition of P—P bonds in P_xO_y, which further degrades the BPNs (Step III). This degradation disrupts the unique structure of BPNs and impairs their functionality.

To address this issue, researchers have proposed various strategies to enhance the stability of BPNs, including physical encapsulation, surface coordination, heteroatom doping, chemical modification, and covalent functionalization. Polyethylene glycol (PEG), polydopamine (PDA), poly(lactic-co-glycolic acid) (PLGA), and nanoparticles (Al₂O₃, SiO₂) are commonly used stabilizing agents, which can not only protect BPNs from the effects of water and O₂ but also preserve their structure and performance^[47]. For instance, after depositing an atomic layer of Al₂O₃ on the surface of BPNs, BPN-based FETs maintained stability for over 8 months^[48]. Similarly, SiO₂-passivated BPN-based FETs retained a high mobility of 470.4 cm²/(V·s) even after being exposed to ambient conditions for one week^[49]. Furthermore, PEG-modified BPNs were prepared based on strong electrostatic adsorption between PEG and BPNs, which not only protected BP but also further improved its biocompatibility^[50].

In addition to physical encapsulation, several methods have been explored to improve the environmental and physiological stability of BPNs. Due to the lone pair of electrons on the P atom, BPNs are highly reactive in air. Surface modification that occupies the active lone pair of electrons has been shown to significantly enhance the stability of BPNs. Zhao et al^[51] designed a titanium sulfonate ligand (TiL₄) to coordinate with BPNs, forming P-Ti coordination bonds, occupying the lone pair of electrons, and protecting BPNs from oxidation. The light absorption intensity of TiL₄@BPNs decreased by only 8% after being dispersed in water for one week, while bare BP decreased by 45%. TiL₄@BPN also maintained structural and morphological stability in air with humidity as high as 95%. Similarly, Xin et al^[52] found that metal ions such as Ag⁺, Fe³⁺, Mg²⁺, and Hg²⁺ spontaneously adsorbed onto the surface of BPNs through cation-π interactions, passivating the lone pair of electrons and enhancing the stability of BPNs.

Heteroatom doping is another simple method to improve the performance of 2D materials by altering their structure^[53]. Wu et al^[54] enhanced the environmental stability of BPNs through tellurium (Te) doping and demonstrated the effect of Te doping via first-principles calculations. Te doping did not change the direct bandgap of BPNs but lowered the band edges, bringing them close to or even below the redox potential of O₂/O₂^-. This reduces the likelihood of photo-induced O₂^- generation, ultimately slowing down the oxidation process.

4 Biomedical Applications

In recent years, researchers have evaluated the biomedical performance of low-dimensional BP, especially in the fields of diagnosis and treatment. Low-dimensional BP has exhibited excellent performance in biomedical research due to its superior near-infrared optical response. Materials based on low-dimensional BP have shown great promise in disease diagnosis, including photoacoustic (PA) imaging^[55], fluorescence imaging^[56], Raman imaging^[57], magnetic resonance imaging (MRI)^[58], computed tomography (CT)^[59], and positron emission CT (PET). In therapeutic strategies, low-dimensional BP plays a versatile agent role and has been widely used in PTT^[60], PDT^[61], ultrasound-mediated therapy^[62], chemotherapy^[63], gene therapy^[64], immunotherapy^[65-66], X-ray-induced PDT^[67-68], and combination therapy strategies^[69]. BP possesses good biocompatibility and degradability, and its degradation products are non-toxic to the human body. In recent years, greater progress has been made in the construction of low-dimensional BP neural networks, and new strategies are expected to make breakthroughs in biomedical research and promote their clinical translation.

4.1 Disease Diagnosis

The diversity of low-dimensional BP networks in disease diagnosis is attributed to their feature of being easily modified. These multifunctional diagnostic patterns are of great significance in clinical research because they can accurately guide treatment progress and prognosis.

4.1.1 Diagnostic Model Based on Low-dimensional BP

Fluorescence imaging is widely used in biological and medical research due to its high sensitivity, spatiotemporal resolution, and rapid feedback^[70]. Low-dimensional BP also exhibits fluorescence imaging capability^[71-72], thus it can be applied to various theranostic models through fluorescent probe labeling strategies^[73-74]. For example, Cy5.5-labeled BP was utilized for monitoring the in vivo biodistribution of BP via fluorescence imaging, precisely guiding targeted chemotherapy, photothermal, and immunotherapy for colorectal cancer^[75]. Fluorescence imaging showed that folate-modified BP induced highly selective accumulation in tumors rather than being retained in other normal tissues (Fig. 7A). The corresponding fluorescence intensity in tumor regions demonstrated that the target group was three times that of the control group, as shown in Fig. 7B. Fluorescent probes in the second near-infrared window (NIR-Ⅱ, 1000-1700 nm) exhibit deeper tissue penetration and higher spatial resolution compared to conventional near-infrared fluorescent probes. A study^[76] reported cholesterol-modified BP nanospheres for in vivo NIR-Ⅱ fluorescence imaging, demonstrating fluorescence imaging emitted by BP over 1400 nm with a higher signal-to-noise ratio than emissions at 810, 1000, and 1250 nm (Fig. 7C). The introduction of fluorescent probe labeling strategies and spontaneous fluorescence strategies has increased the application prospects of low-dimensional BP algorithms in bioimaging.

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图7 （A）Cy5.5-标记的BP在没有FA和具有FA的情况下在心脏、肝脏、脾脏、肺和肾脏中的离体生物分布；（B）相应的荧光强度；(C)填充有BP@lipid-PEG纳米球水溶液并覆盖有不同厚度的鸡胸切片的毛细管的光致发光图像，由不同波长的光学滤波器捕获。沿沿着黄色虚线的横截面荧光信号强度曲线显示在顶部。比例尺：5 mm^[75]

Fig. 7 (A) Ex vivo biodistributions of Cy5.5-labeled BP without FA and with FA in heart, liver, spleen, lung, and kidney; (B) corresponding fluorescence intensities; (C) Photoluminescence images of a capillary filled with BP@lipid-PEG nanosphere aqueous solution and covered with the chicken breast slice with different thicknesses, captured by different wavelength optical filters. Cross-sectional fluorescence signal intensity profiles along yellow dotted lines are shown at the top. Scale bar: 5 mm^[75]

Unlike traditional optical imaging, PA imaging is a promising non-invasive biological imaging strategy with deeper tissue penetration, which is attributed to the light absorption coefficient of the imaged tissue^[77]. Therefore, compared with other biological imaging modalities, PA imaging has excellent spatiotemporal resolution, high sensitivity, and an outstanding signal-to-noise ratio^[78]. Contrast agents with high light absorption coefficients can absorb the light energy of external lasers and subsequently convert it into thermal energy. The local thermoelastic expansion associated with instantaneous temperature rise and synchronous ultrasound emission can be converted into PA images by an ultrasound (US) transducer^[79]. Low-dimensional BP has a large extinction coefficient and excellent photothermal conversion efficiency^[80], which provides excellent PA imaging capability^[81]. Therefore, most low-dimensional BPs with PA show good prospects in bioimaging applications^[82]. There have been various reports on the research of low-dimensional BP-based PA nanoagents to improve their PA performance in theranostics^[83⇓-85]. For example, polydopamine (PDA)-coated BPQDs (BP@PDA) exhibit enhanced PA imaging performance compared with bare BPQDs^[86]. Considering the significant laser scattering effect, the light intensity and PA signal-to-noise ratio decrease exponentially with increasing tissue depth; thus, obtaining PA imaging contrast with tissue penetration or designing clever strategies to improve PA imaging performance in deep tissues is highly useful.

Surface-enhanced Raman scattering (SERS) spectroscopy is a label-free analytical method that can provide first-hand molecular fingerprint information for physiological or pathological identification^[87-88]. The characteristic Raman peaks of BP are all located below 500 cm^-1, without background interference in the fingerprint region (600-1800 cm^-1)^[89]. Therefore, 2D BP is a promising alternative substrate, and its integration with other noble metal components can be used for biological SERS analysis^[90]. For example, Liu et al.^[91] reported a black phosphorus-gold nanoparticle hybrid (BP-AuNPs) for label-free living cell bioimaging. The SERS spectra of the tested cancer cells showed different spectra, describing changes associated with the photothermal effect. Thus, SRES imaging can monitor the prognosis of cancer treatment. During the photothermal ablation process, the SERS signals of proteins (1004 cm^-1), DNA/RNA (815 cm^-1), lipids (700 cm^-1), and carbohydrates (883 cm^-1) were redistributed, showing significant changes in cancer cells.

4.1.2 An Improved Feature-Based Diagnostic Model

MRI is a powerful bioimaging technique in clinical settings, offering advantages such as non-invasiveness, deep tissue penetration, and clear imaging capabilities^[92]. Many researchers^[93⇓-95] have attempted to combine MRI with low-dimensional BP biomaterials. For example, Guo et al.^[96] reported a tannic acid (TA) coating strategy for preparing BPNS-based nanoplatforms while chelating Mn²⁺ (BPNS@TA-Mn), which exhibits MRI T₁ and contrast enhancement performance (Figure 8A). This system maintains a flake-like morphology (Figure 8B) and demonstrates high Mn²⁺ loading rates (Figure 8C). Similar to Gd-DTPA, BPNS@TA-Mn generates concentration-dependent T₁ contrast signals (Figure 8D), and the longitudinal relaxation rate (r₁) value of BPNS@TA-Mn is higher than that of Gd-DTPA (Figure 8E). Wu et al.^[97] introduced a TME-responsive BP/MnO₂ nanomaterial with MRI capabilities. After intravenous injection of BP/MnO₂, the MRI signal of the tumor increases with prolonged incubation time (Figure 8F), and ex situ T₁-weighted MRI also indicates good tumor microenvironment responsiveness due to tumor-specific accumulation in BP/MnO₂ (Figure 8G). Therefore, rapid and precise tumor-specific MRI obtained through BP/MnO₂ can guide accurate cancer treatment.

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图8 (A)使用BPNS@TA-Mn的MRI/PA双模式成像引导PTT的应用示意图；(B)TEM图像；(C)EDX映射图像；(D)BPNS@TA-Mn与不同金属浓度的Gd-DTPA的T1加权体模图像比较；(E)纵向弛豫率的线性拟合；(F)BPN/MnO₂/ DOX注射后荷瘤小鼠体内MRI；(G)相应的时间依赖性T1值变化^[96]

Fig. 8 (A) Schematic for the application of MRI/PA dual-modal imaging-guided PTT using BPNS@TA-Mn; (B) TEM image; (C) EDX mapping image; (D) T1-Weighted phantom images of BPNS@TA-Mn compared to Gd-DTPA with different metal concentrations; (E) The linear fitting of longitudinal relaxation rates; (F) In vivo MRI of mice bearing HeLa tumor after the injection ofBPN/MnO₂/DOX; (G) corresponding time-dependent T1 value changes^[96]

4.2 Treatment Strategies

BP and black phosphorus analogs nanomaterials (BPAs) containing non-toxic elements (e.g., Sn, Te, Sb, and Bi) and their mixed 2D nanomaterials have shown promising prospects in various biomedical applications^[98], primarily in cancer treatment. For instance, several 2D Te systems have been utilized as drug carriers, photosensitizers (PS), and photothermal agents for cancer therapy^[99⇓-101]. Lin et al.^[102] were the first to explore free-standing 2D Te NSs with strong absorption in the NIR region via a facile liquid-phase exfoliation method, which kill cancer cells by generating ROS at the tumor site under 670 nm irradiation. Polymer functionalization can overcome certain limitations (e.g., poor biostability and poor biocompatibility) to significantly enhance their synergistic therapeutic effects in biomedical applications^[103]. Due to their inherent unique properties, high PTCE, and specific clearance pathways, various cancer treatment strategies involving BPAs/polymers mainly focus on traditional drug delivery and release, PDT, and PTT.

4.2.1 Phototherapy

As an alternative to traditional cancer treatments (such as chemotherapy and surgery), phototherapy can effectively generate local heat or cytotoxic ROS under light irradiation to induce cancer cell death, mainly including PTT and PDT. BP-based nanomaterials^[104], due to their tunable bandgap and wide range of light absorption^[105], can be used as potential PDT and PTT agents in cancer phototherapy research. The size of BP has the most significant impact on PDT or PTT performance. Fu et al.^[106] prepared BPNSs of different sizes, namely L-BP (394 nm), M-BP (118 nm), and S-BP (4.5 nm), and studied their photothermal capabilities. The results showed that the PTCE value of L-BP was higher than that of M-BP and S-BP, with extinction coefficients being L-P (32.5 L/(g·cm)), M-BP (21.79 L/(g·cm)), and S-BP (15.43 L/(g·cm)) respectively. Moreover, in vitro experiments demonstrated that larger-sized BPNSs have better photothermal efficiency for cancer cell ablation. Under physiological conditions, the stability and biocompatibility of BP in phototherapy can be effectively improved by compositing with polymers. Compared with bare BP, BP/polymer can play a more effective synergistic anti-cancer role in phototherapy. In addition, BP/polymer nanocomposites have been used as drug delivery platforms to load chemotherapy or gene drugs, owing to the high specific surface area of BP and its photothermal/acidic response, which can promote drug release in cancer tissues.

4.2.1.1 PTT

PTT has the advantages of being highly efficient, minimally invasive, and highly selective, utilizing photoabsorbers to induce thermal shock in tumor cells under light irradiation, making them more prone to apoptosis; this strategy has garnered significant attention in cancer treatment within preclinical research^[106-107]. Compared with various graphene analogs used for tumor thermotherapy in recent years (such as 2D TMD and MXenes), 2D BP nanomaterials possess high PTCE (high photothermal conversion efficiency) and a strong extinction coefficient. Moreover, BP/polymer demonstrates broad absorption across the entire visible light spectrum and has been utilized as an anti-tumor PTT agent.

In 2015, Bondarenko et al^[108] synthesized PEG-coated BPQDs (BPQD/PEG) with excellent photothermal properties and negligible cytotoxicity. BPQDs were prepared by liquid exfoliation under multidimensional ultrasonic treatment. PEGylated BPQDs exhibited high stability both in vitro and in vivo. When exposed to NIR laser for 10 minutes, the temperature of the BPQD solution (50 ppm, 1 ppm=1×10^-6) increased by 31.5 ℃ due to its good PTCE of 28.4%. In in vitro experiments, only 50 ppm (1 ppm=1×10^-6) BPQD/PEG could kill all MCF7 cancer cells under NIR light irradiation. Additionally, Sun et al^[109] prepared PEGylated BPNPs with excellent photostability and biocompatibility through a traditional high-energy mechanical milling (HEMM) technique as PTT agents for cancer treatment. Intratumoral injection of PEGylated BPNPs followed by 5 minutes of NIR laser irradiation rapidly increased the temperature of the tumor area in vivo to 59 ℃, which could lead to apoptosis of tumor cells without recurrence. Moreover, solid tumors in mice treated with PEGylated BP nanoparticles and laser irradiation shrank and gradually crusted after 3 days of treatment. All mice survived for more than 42 days. These results indicate that PEG can effectively improve the biocompatibility and stability of BP both in vitro and in vivo.

To enhance the therapeutic efficacy of BP, other biocompatible materials have also been utilized for PTT under physiological conditions. Shao et al^[110] prepared BPQDs/PLGA by encapsulating BPQDs into PLGA. PLGA played a crucial role in maintaining the stability of internal BPQDs in the physiological environment and promoting the properties of BP as a PTT agent in cancer treatment (Figure 9A). Even at a higher concentration of 100 ppm, BPQDs/PLGA NSs did not exhibit significant cytotoxicity to normal cells and tumor cells, and their irradiation with an 808 nm laser (1 W/cm²) for 10 minutes could effectively ablate deep MCF7 and B16 tumor cells without any obvious side effects, demonstrating their high PTT efficiency. After the injection of BPQDs/PLGA NSs for 24 hours, the temperature at the in vivo MC7 breast tumor site increased to 58.8 ℃ under 880 nm NIR laser irradiation, which was sufficiently high to kill tumor cells (Figure 9B and C). More importantly, all treated mice were completely cured within 16 days and survived for more than 40 days (Figure 9D). The success of this method provides a reference for subsequent research on deep tumors and clinical PTT.

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图9 （A）BPQDs/PLGA NSs的制备和降解过程；(B)荷瘤小鼠近红外线照射后的红外热像图；（C）温度变化曲线；(D)BPQDs/PLGA NSs + NIR治疗后的肿瘤体积变化^[109]

Fig. 9 (A) Preparation and degradation processes of BPQDs/PLGA NSs; (B) Infrared thermographic image; (C) temperature variation curve in tumorbearing mice after NIR irradiation; (D) Tumor volume changes after BPQDs/PLGA NSs + NIR treatment^[109]

In 2018, Shao et al^[110] prepared a biocompatible and injectable 3D network cellulose/BPNSs hydrogel based on polymer cellulose and BPNSs for PTT anticancer (Figure 10 A). The hydrogel exhibited excellent PTCE, good flexibility, and enhanced stability. All cell lines in the models could be killed at a concentration of 380 ppm BPNSs/cellulose hydrogel, and the high thermal conversion from NIR irradiation led to high tumor cell killing efficiency (Figure 10B). The temperature at the tumor site of tumor-bearing mice treated with BPNSs/cellulose hydrogel and near-infrared radiation could reach up to 64.1 ℃ in a short period of time at a high speed, higher than the temperature (41.2 ℃) without BPN_S, which was sufficient to kill tumor cells. Additionally, after the combined action of BPNSs/cellulose and NIR irradiation, the tumor volume and body weight of tumor-bearing mice were slightly reduced, indicating its excellent PTT effect on tumor cells (Figure 10 C and D). It is significant to utilize BP-based nanomaterials using natural cellulose polymers as PTT agents for cancer treatment, and this material is worthy of research and reference, providing insights for future applications in clinical settings to combat cancer.

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图10 （A) 纤维素/BPNSs水凝胶的合成；(B)不同给药组的体温变化；(C)不同组别治疗后肿瘤体积随时间的变化；(D)四组小鼠体重的变化^[110]

Fig. 10 (A) Synthesis of cellulose/BPNSs hydrogels; (B) Temperature changes in different treatment groups; (C) Time-dependent tumor volume changes after treatment with different groups; (D) Changes in mouse weights for the four groups^[110]

The heat generated by PTT can be used to induce cancer cell lesions through thermography^[110], which is utilized for inducing treatment and represents an additional benefit in disease therapy. So far, various BP/polymer or BPA/polymer nanomaterials as photothermal agents have been applied in PTT for cancer cell death triggered by hypertension. However, the side effects associated with the in vivo use of such materials have not been thoroughly studied, such as potential inflammation, damage to normal cells, or induction of metastasis. Therefore, there is still a significant amount of research work to be done regarding the application of BP/polymer in PTT.

4.2.1.2 PDT

PDT has been clinically approved for treating patients who do not want to undergo surgery and routine examination (RT) due to its good repeatability, low systemic toxicity, and excellent selectivity. The key factor leading to tumor cell death by PDT treatment is the production of large amounts of reactive oxygen species (ROS) by PS under appropriate light irradiation, where ROS kill tumor cells without damaging neighboring healthy tissues. Compared with traditional PS, BP/polymer-based PS possesses several advantages (e.g., safety, effective intracellular translocation, and biodegradability) as a potential PS for PDT.

To increase the penetration depth of visible light and enhance the efficacy of PDT, Lv et al^[111] designed and prepared a phototransformation composite based on upconversion nanoparticles (UCNPs) and bisphosphonate BPNSs (BPNSs/UCNPs) as a PDT agent for the first time. This composite was synthesized by combining polyacrylic acid (PAA)-modified UCNPs with polyethylene glycolated BP through electrostatic interactions. Both extracellular and intracellular experiments demonstrated that compared to the results using 650 nm and 980 nm irradiation, the use of BPNSs/UCNPs composites with 808 nm NIR light irradiation generated ROS at the maximum rate to inhibit tumor cell viability. The toxicity of BPNSs/UCNPs + 808 nm laser irradiation on normal cells was weak. After 14 days of 808 nm light irradiation, the HeLa cells in tumor-bearing mice were completely inhibited and killed. Meanwhile, the nanoparticles had no side effects, and the mice's bodies continued to grow normally, indicating that BPNSs/UCNPs have excellent anti-tumor effects as PSs. This work developed a new method for using PDT to treat cancer, where the complementary effects of BPNSs/UCNPs composites with PAA and PEG polymers accelerate tumor cell apoptosis or death by enhancing ROS production.

Moreover, BPQDs exhibited antitumor effects similar to those of BPNSs. In 2018, Guo et al^[112] were the first to prepare PEGylated BPQDs with a diameter of 5.4 nm as PSs for PDT cancer treatment (Figure 11A). Both bare BPQDs and PEGylated BPQDs showed no significant cytotoxicity in vivo, had good biocompatibility, and were suitable for biomedical applications. Using 1,3-diphenylisobenzofuran (DPBF), it was detected that PEGylated BPQDs could effectively sustain ^[113] ROS production under 670 nm light irradiation for a certain period of time (Figure 11B). PEGylated BPQDs could efficiently generate intracellular ROS to kill most tumor cells within a short time under 670 nm irradiation (Figure 11C). Furthermore, after injection of PEGylated BPQDs and 670 nm irradiation for 16 days, the growth of S180 tumors in mice was strongly inhibited, with minimal relative volume (Figure 11D). More importantly, over 65% of the BPQDs were excreted via urine within 8 hours after intravenous injection. This work provides the first validation of using BPQDs/polymers as strong PDT PSs for cancer treatment and also allows for investigation into the structural changes of PEGylated BPQDs in the blood.

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图11 （A）PEG化BPQDs在PDT中的潜在应用的介绍^[112]；(B)用PEG化BPQDs孵育后HeLa和L02细胞的浓度和细胞活力依赖性；(C)用DCFH-DA + PEG化BPQDs+光照射孵育的HeLa细胞的荧光显微镜图像；(D)不同处理后的肿瘤生长曲线

Fig. 11 (A) Introduction of potential applications of PEGylated BPQDs in PDT^[112]; (B) Concentrations and cell viability dependence of HeLa and L02 cells after incubation with PEGylated BPQDs; (C) Fluorescence microscope images of HeLa cells incubated with DCFH-DA + PEGylated BPQDs + light irradiation; (D) Tumor growth curves after different treatments

Generally, high ROS levels and hypoxia in the tumor microenvironment (TME) are not conducive to achieving better PDT effects for cancer treatment. Catalyzing high hydrogen peroxide in the TME to produce a large amount of O₂ is an effective strategy to overcome hypoxia by enhancing PDT for cancer treatment. Currently, PDT has become a widely accepted clinical treatment method due to its advantages of low toxicity, minimal side effects, less trauma, and low invasiveness, and can be used to treat various diseases such as genital warts, facial skin cancer, retinoblastoma, hemangioma, oral cancer, and so on. Polymer modification can overcome certain limitations of BPA itself and traditional PDT (e.g., poor targeting, low photostability, and poor biocompatibility) for cancer treatment.

4.2.1.3 Combination of PTT and PDT

In recent years, phototherapy has attracted increasing attention due to its minimal invasiveness during the cancer treatment process and its ability to overcome certain drawbacks of surgical resection, chemotherapy, and RT. The synergistic phototherapy of tumors not only enhances the respective advantages of PTT and PDT but also overcomes their shortcomings. BP/polymer can act as a photothermal agent and PS because BP can induce extremely high temperatures under NIR irradiation to promote blood circulation, thereby increasing oxygen levels around tumor tissues and the cellular uptake efficiency of BP/polymer, indicating that PDT and PTT can enhance each other to provide excellent synergistic therapeutic effects. Therefore, the combination of PTT/PDT has been extensively studied. For instance, Li et al^[114] developed PEGylated BPQDs as multifunctional PTT and PDT agents for cancer treatment. The prepared nanoparticles exhibited excellent near-infrared photothermal performance and ¹O₂ generation capability, which significantly suppressed tumor growth in vivo. Systematic histological analysis confirmed the low cytotoxicity of this therapeutic agent and negligible side effects on major organs of mice.

Yang et al^[115] synthesized bifunctional Te NDs (with a diameter of 5.9 nm) through the controlled reduction reaction of NaBH₄ in the template of human serum albumin (HSA) polymer nanocages (Figure 12A). Under NIR irradiation, Te NDs/HSA endocytosed into lysosomes generate a considerable amount of ROS, including ·O₂^- and ·OH, via a Type I mechanism by forming photoexcited electrons from the valence band to the conduction band in aqueous solution (Figure 12B). Subsequently, the lysosomal membrane is disrupted by ROS, and other components in the cytoplasm are damaged by the photodynamic cytotoxicity of Te NDs to provide ROS, ultimately leading to the death of 4T1 mouse breast cancer cells. The results showed that due to the EPR effect of Te NDs/HSA and the tumor accumulation capability of HAS, Te NDs/HSA were highly distributed in tumors and the liver in vivo after intravenous injection into 4T1 tumor-bearing mice. Fortunately, Te NDs/HSA with ultra-small sizes were effectively cleared to avoid their long-term retention in normal tissues (Figure 12C). In mice injected with Te NDs/HSA, the maximum temperature difference at the tumor site under 785 nm irradiation reached up to 20 ℃; additionally, ROS were detected in this area using dihydroethidium (DHE) staining, indicating strong photothermal and photodynamic efficiency (Figure 12D). The abundant ROS and high temperature at the tumor site in vivo contributed to the ablation of cancer cells without any regrowth (Figure 12E), confirming the excellent synergistic apoptotic efficacy of PDT and PTT in cancer treatment. Therefore, Te NDs are the prerequisite PSs and photothermal agents for achieving synergistic photosensitive cancer therapy under NIR irradiation while ensuring no damage to normal tissues in vivo. HSA provides a stable environment and ideal tissue transparency effect.

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图12 （A）双功能Te NDs的制备；(B)近红外诱导Te NDs产生ROS的机制；(C)细胞内协同处理的示意图；(D)Te NDs的曲线可以产生活性氧；(E)不同治疗组小鼠的肿瘤体积变化^[115]

Fig. 12 (A) Preparation of bifunctional Te NDs; (B) NIR-induced mechanism of Te NDs for ROS generation; (C) Schematic of intracellular synergistic treatments; (D) Curve of Te NDs can generate ROS; (E) Tumor volume changes in mice for different treatment groups^[115]

Yang et al^[116] synthesized BPNSs@PEG/Ce6 based on BPNSs and chlorin e6 (Ce6), constructing a synergistic thermography-guided PTT/PDT theranostic platform. The BPNSs prepared by the liquid exfoliation of bulk BP were successfully modified with PEG-NH₂ and Ce6 to enhance their biocompatibility and light absorption capability (Figure 13A). Compared with BPNSs@PEG (28.7%), BPNSs@PEG/Ce6 exhibited a 43.6% higher PTCE (Figure 13B). Moreover, in vitro studies confirmed that under 660 nm laser irradiation, BPNSs@PEG/Ce6 NS could efficiently generate a higher amount of intracellular ROS within 10 minutes and prolong the PDT treatment time due to the slow release of Ce6 (Figure 13C). Meanwhile, after the injection of BPNSs@PEG/Ce6, the temperature around the tumor area increased from 36.6 ℃ to 46.8 ℃ (Figure 13D). After injecting BPNSs@PEG/Ce6 and treating with 660 nm irradiation, the tumor tissues of the mice were completely destroyed after 14 days without any significant toxic side effects (Figure 13E).

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图13 （A）用于癌症治疗的BPNSs@PEG/Ce6 NS制备和PDT/PTT的总结；(B)不同溶液组的温度变化；(C)不同组的体内光热效应；(D)不同组的体内抗肿瘤作用；(E)不同处理组的小鼠体重变化^[116]

Fig. 13 (A) Summary of BPNSs@PEG/Ce6 NS preparation and PDT/PTT for cancer therapy; (B) Changes in the temperature for the different solution groups; (C) In vivo photothermal effect for the different groups; (D) In vivo antitumor effect for the different groups; (E) Changes in mice weights for the different treatment groups^[116]

4.2.1.4 Combined PTT and Chemotherapy

In recent years, reducing the number of administrations and total dose of chemotherapy and RT in clinical tumor treatment has become a research hotspot. Multifunctional BPAs/polymer nanocomposites synergistically enhance PTT compared to conventional methods, significantly improving therapeutic effects while avoiding damage to normal tissues, such as photothermal-enhanced chemotherapy^[117] and photothermal-enhanced RT^[118]. Near-infrared light can improve cellular uptake and release of chemotherapeutic drugs, thereby significantly reducing side effects and enhancing anti-tumor efficiency.

2D Te/polymer nanocomposites exhibit promising photothermal effects by converting near-infrared radiation into high heat and increasing intracellular ROS levels, but clinical trials still have a long way to go. 2D Te nanomaterials and polymers are complementary in achieving tumor suppression. Huang et al^[119] prepared fructose (Fru) and Na₂TeO₃ through a reduction reaction between them to create polysaccharide-protein complex (PTW)-modified Te nanorods (PTW-Te NRs) with a length of 95.2 nm (Figure 14A). PTW is not only an anti-tumor therapeutic agent but also a stabilizer for natural drugs. This nano-system was used as a chemo-photothermal agent against tumors. The PTW composed of proteins and polysaccharides demonstrates advantages in anti-cancer activity and nutrition, which also maintains the high monodispersity and long-term stability of Te NRs under physiological conditions for at least 80 days (Figure 14B). The PTCE (37.4%) of PTW-Te core reactors is higher than that of common photothermal agents Au (PTCE 22%). In vitro experiments show that under continuous 808 nm light irradiation, intracellular hyperthermia (maximum temperature: 68.2 ℃) inhibits the growth of different cancer cells (HepG2, A375, and HeLa) without harming normal cells (Figure 14C). Meanwhile, in vitro PDT experiments indicate that PTW-Te NRs can rapidly generate large amounts of intracellular ROS under NIR irradiation, leading to cancer cell apoptosis. As shown in Figure 14D, the temperature of tumors in mice injected with PTW-Te NRs rapidly increased to 65.3 ℃ under 808 nm laser irradiation, resulting in complete tumor death; more importantly, the tumors gradually disappeared, and no recurrence was observed after 21 days (Figure 14E). Furthermore, during the treatment period, no toxic side effects were detected in the major organs (heart, liver, spleen, lung, and kidney) of the recovered mice, indicating that selective induction of cancer cell apoptosis is a promising method for cancer PTT and PDT. The results show that the combined treatment group of PTW-Te NRs and NIR light achieved the best therapeutic effect.

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图14 （A）Te NPs和PTW-Te NRs的制备和协同癌症治疗过程；(B)NIR照射下PTW-Te NPs溶液的温度；(C)不同细胞的IC50值；(D)不同治疗组肿瘤内注射的肿瘤部位的IR图；(E)不同治疗组的肿瘤体积^[119]

Fig. 14 (A) Preparation and synergistic cancer therapy process of Te NPs and PTW-Te NRs; (B) Temperature of PTW-Te NPs solution under NIR irradiation; (C) IC50 values of different cells; (D) IR maps of tumor sites with intratumoral injections for different treatment groups; (E) Tumor volumes for the different treatment groups^[119]

4.2.1.5 Cooperative PTT and RT

Similar to chemotherapy, RT is another method in clinical cancer treatment. Side effects and hypoxia are serious issues that weaken its efficacy^[120]. Some polymer-modified metal nanomaterials, as excellent radiosensitizers (e.g., Bi₂Se₃/PVP, AuNPs/PEG, and TaO_x@PEG), can enhance the efficacy of RT while minimizing potential damage to normal tissues. Additionally, mild hyperthermia enhances the tumor-killing efficacy of RT by increasing oxygen levels in tumor tissues^[121]. Typically, semi-metal element/polymer nanomaterials with radiation and photothermal properties have been utilized as multifunctional agents for effective cancer theranostics in biomedical applications^[122-123]. For instance, Yu et al.^[124] reported ultra-small tumor-targeted PEGylated and peptide-labeled bismuth nanoparticles (3.6 nm) for synergistic PTT/RT in cancer treatment. The preparation process of PEGylated Bi-LyP-1 NPs involves a simple reduction reaction, PEG modification, and LyP-1 functionalization sequentially (Figure 15A). This nano-system exhibits excellent properties, including good photothermal effects within the NIR-II window with a PTCE value of 32.2% under 1064 nm laser irradiation (Figure 15B), good photostability and chemical stability under physiological conditions, and low long-term toxicity due to surface modification and ultra-small size (12 nm). Due to the tissue specificity of PEG and tumor targeting of LyP-1, PEGylated Bi-LyP-1 NPs show a 2.4-fold higher cellular uptake efficiency and a 1.7-fold higher accumulation in 4T1 cancer cells compared to unlabeled BiNPs. Furthermore, after intravenous injection of Bi-LyP-1 NPs in vivo, CT imaging signals and high PA signals at the tumor sites in mice were significantly enhanced. Notably, the combination of intratumoral injection of Bi-LyP-1 NPs, 1064 nm laser irradiation, and 4Gy X-ray irradiation resulted in more effective tumor suppression than other combinations (Figure 15C). The nanoparticles were almost completely cleared via renal and fecal mechanisms 30 days post-injection with nearly no residue. These results indicate that PTT and RT have significant synergistic effects, and Bi-LyP-1 NPs serve as excellent multifunctional targeted PS and radiosensitizers.

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图15 （A）PEG化Bi-LyP-1的制备和功能；(B)与不同治疗组联合后激光照射下小鼠的IR图谱；(C)不同治疗组的肿瘤体积曲线^[124]

Fig. 15 (A) Preparation and functions of PEGylated Bi-LyP-1; (B) IR maps of mice under laser irradiation after combining with different treatment groups; (C) Curves of tumor volumes for the different treatment groups^[124]

4.2.2 Drug Delivery Systems (DDSs)

DDSs can prevent certain issues associated with the use of conventional drugs, such as poor water solubility and dosing frequency, while achieving therapeutic effects^[125]. Biodegradable BP-based DDSs represent one of the most promising approaches for cancer and other disease treatment by accumulating at tumor sites and controlling drug release to achieve therapeutic effects^[126]. Moreover, BP/polymer can modify BP-based DDSs to respond to drugs carried in the tumor cell microenvironment for cancer therapy, thereby enhancing their in vivo instability and targeting ability^[127-128].

4.2.2.1 Delivery of Chemotherapeutic Agents

Chemotherapy drugs are an inexpensive and convenient method for cancer treatment. However, the drawbacks of broader distribution and side effects on healthy tissues make them unsuitable for long-term application. Emerging BP/polymer as carriers for chemotherapy drugs can significantly enhance efficiency and reduce certain side effects, such as specific targeting release at tumor sites and the uptake efficiency of drugs.

PEG-modified BP nanosheets possess excellent physiological stability and are promising robust drug delivery platforms in biological applications. In 2016, Tao et al^[129] fabricated novel theranostic DDSs based on polyethylene glycol (PEG)-functionalized BP nanosheets with a maximum loading capacity of the anticancer drug doxorubicin (DOX) at 108% (PEG-BP/DOX NSs), which is much higher than the loading capacities reported for many NP-based material systems (10%-30%). Additionally, PEGylated BPNSs were further enhanced with PEG fluorescent imaging agents (BPPEGFITC), Cy7 dye (BP-PEG/Cy7), and targeting moieties such as folic acid (FA-BP-PEG) for screening endocytic pathways, bioimaging, and site-specific therapeutic agent delivery, respectively (Figure 16 A). Bio-colocalization studies confirmed that PEGylated BPNSs carry drugs interacting with the cytoplasmic membrane via caveolae-mediated endocytosis and macropinocytosis pathways into cancer cells (Figure 16 B). Synergistic experiments involving photothermal and MTT assays demonstrated that FA-BP-PEG/DOX NSs with cancer recognition capability can effectively destroy tumor cells at lower DOX concentrations (5 μg/mL). Through Cy7 fluorescence imaging, PEGylated BP nanosheets showed good accumulation in tumor tissues after 24 hours of incubation. In vivo anti-tumor experiments confirmed that repeated injections every two days of a certain dose of BPPEG/DOX NSs significantly reduced tumor growth after two weeks of 808 nm laser irradiation without damaging normal tissues, due to the sustained antitumor effects of PEGylated BP combined with biologically responsive induced therapy, chemotherapy, and PTT (Figure 16 C). Therefore, PEG-modified BPNSs, as carriers for tumor therapeutics, exhibit excellent biosafety, controllable drug release, flexible modification, and low cytotoxicity, offering broad application prospects.

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图16 （A）作为药物递送平台的PEG化BP的示意图；(B)PEG化BP的DOX负载能力；(C)24 h后通过静脉内注射的PEG化BPNSs的体内NIR成像^[129]

Fig. 16 (A) Schematic of PEGylated BP as the drug delivery platform; (B) DOX loading capacities of PEGylated BP; (C) In vivo NIR imaging of PEGylated BPNSs via intravenous injection after 24 h^[129]

In 2018, Liu et al^[130] developed a smart NIR light-responsive drug release hydrogel system (DOX/BP@hydrogel) based on the polymer agarose loaded with the anticancer drug (DOX), which softens at 40-45 ℃ and melts at 45-50 ℃. After injection of DOX/BP@hydrogel, it can be accurately released into the tumor tissue to achieve effective treatment, while the local hyperthermia generated under near-infrared light irradiation kills cancer cells. Notably, the biodegradable and biocompatible DOX/BP@hydrogel platform exhibits good potential in breast cancer and melanoma treatment under NIR laser. Therefore, it is necessary to prepare BP nanomaterials with long-term stability, higher quality, and better thermal properties as a drug delivery platform.

The development of precise multifunctional BP/polymer-based nanomaterials for the effective treatment of primary and lung metastatic tumors remains a significant challenge. In 2019, Wang et al^[131] successfully designed and synthesized a biocompatible and multifunctional "Trojan horse" nanomedicine that combines BPQDs and docetaxel (DTX) encapsulated in PLGA polymer (BP/DTX@PLGA) (Figure 17A). PLGA can protect BP from rapid degradation under physiological conditions. Additionally, the loaded DTX and coated PLGA do not affect the PTCE of the BP material. When the temperature rapidly increased to 45°C, the release of DTX in the complex increased, and after 10 minutes of irradiation with an 808 nm near-infrared laser, the composite caused tumor cell death due to its excellent photothermal effect. Due to the enhanced EPR effect caused by PLGA microencapsulation, BP/DTX@PLGA has a robust ability to target both primary and metastatic tumors (Figure 17B). Meanwhile, the photothermal effect significantly enhanced the tumor growth inhibition efficacy of BP/DTX@PLGA (Figure 17C). Bioluminescence detection confirmed that BP/DTX@PLGA injection and NIR synergistic treatment greatly inhibited metastatic tumor growth (Figure 17D).

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图17 （A）BP/DTX@PLGA NSs的制备和治疗过程的示意图；（B）和（C）注射BP/DTX@PLGA NSs后原发性肿瘤和肺转移性肿瘤的检测；(D)不同处理组的4T1-LG12细胞的细胞活力^[131]

Fig. 17 (A) Schematic of the preparation and therapeutic processes of BP/DTX@PLGA NSs; (B) and (C) Detection of primary tumors and lung metastatic tumors after BP/DTX@PLGA NSs injection; (D) Cell viabilities of 4T1-LG12 cells for the different treatment groups^[131]

4.2.2.2 Delivery of Gene Reagents

The gene silencing of tumor cells induced by small interfering RNA (siRNA) is a major strategy in gene therapy. For a long time, naked siRNA has had the disadvantages of poor specificity, low efficiency of cellular uptake, and rapid enzymatic degradation in the biological body, which is not conducive to clinical applications. The targeted delivery strategy of siRNA-mediated gene silencing is a feasible solution to the above problems. Therefore, it is necessary to develop safe and effective siRNA nanocarriers to prevent their rapid enzymatic degradation under serum conditions^[132]. BP/polymer, with a high specific surface area, negative charge, and non-toxic characteristics, can be used for siRNA delivery to meet transportation needs. BP/polymer can also transport DNA components encoding the Cas9 protein and single guide RNA (sgRNA) complex into cancer cells, achieving efficient genome editing and gene silencing.

In 2017, Yin et al^[133] reported the use of polyethylene polymer (PAH)-modified BPQDs (BPQDs@PAH) as a novel siRNA delivery platform and photothermal agent into human ovarian teratocarcinoma (PA-1) cells to inhibit cancer stem cells (Figure 18A). The BPQDs@PAH/siRNA nanocomplex can effectively transport siRNA into cancer cells and induce gene knockdown, achieving a high transfection efficiency of 92.7% for treating PA-1 cells, which is significantly higher than the transfection efficiency obtained using other delivery agents such as oligofectamine and Lipo 2000 (Figure 18B). The inhibition rate of BPQDs@PAH/siRNA on PA-1 cell growth exceeds 80%. Importantly, BPQDs show good biocompatibility and low cytotoxicity even at a higher mass concentration of 5 mg/mL, meeting the requirements for clinical research applications in cancer treatment (Figure 18C).

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图18 （A）制备新的功能性BPQDs@基于PAH的siRNA递送系统的示意图；(B)不同处理组PA-1细胞转染效率的流式细胞术评价；(C)不同处理组的PA-1细胞的相对细胞活力^[133]

Fig. 18 (A) Schematic of the preparation of novel, functional BPQDs@PAH-based siRNA delivery systems; (B) Flow cytometry evaluations regarding the transfection efficiencies of PA-1 cells for the different treatment groups; (C) Relative cell viabilities of PA-1 cells for the different treatment groups^[133]

To reduce the side effects of BP/polymer during siRNA transport in vivo, Wang et al^[134] reported positively charged PEI-modified BPNS as an siRNA delivery system for cancer therapy (BP-PEI-siRNA) (Figure 19A). Under the protection of BP-PEI, enzymatic degradation of siRNA was prevented, improving gene transfection efficiency. Cancer cells exhibited an apoptosis rate exceeding 64% in vitro, which is higher than the inhibitory rate of naked survivin siRNA (44%), due to the excellent photothermal performance and synergistic PTT and gene therapy of the BP-PEI-siRNA combination (Figure 19B). After treatment with BP-PEI-siRNA and NMR laser irradiation, tumor cell growth was significantly inhibited, and Survivin protein expression was downregulated. Meanwhile, no side effects or long-term safety issues were observed during BP-PEI-siRNA treatment (Figure 19C). PEI can effectively enhance the stability of BP and the delivery capacity of siRNA, thereby increasing gene transfection efficiency.

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图19 （A）BPNSs-PEI-siRNA和协同PTT和基因疗法的制备过程的示意图；(B)用不同组处理后的细胞活力测定；(C)不同处理组的肿瘤生长曲线^[134]

Fig. 19 (A) Schematic of the preparation process of BPNSs-PEI-siRNA and synergistic PTT and gene therapy; (B) Cell viability assay after treating with different groups; (C) Curves of tumor growth for the different treatment groups^[134]

To improve the low specificity and inefficiency of siRNA delivery and release caused by the single anticancer effect of gene silencing, Chen et al^[135] reported biodegradable BPNSs as a specific delivery platform for hTERT siRNA combined with PTT to reduce tumor growth and metastasis. BPNSs were prepared by liquid exfoliation method, followed by modification with PEG and PEI polymers (PPBP-siRNA) (Figure 20A). PPBP-siRNA exhibited optimal inhibition of tumor cell growth under laser irradiation, initially at 808 nm, followed by 660 nm, due to the increased intracellular heat and ROS generated under 660 nm irradiation (Figure 20B). In cancer cells, siRNA was released from PPBP-siRNA while a large amount of ROS was generated under NIR irradiation; furthermore, PPBP gradually degraded during this process through the generation of ROS. After intravenous injection of PPBP-siRNA, the temperature of tumor tissue increased from 4.2 ℃ to 49.7 ℃ within 5 minutes under 808 nm irradiation (Figure 20C). Notably, in vivo experiments showed that due to the effective synergy among PTT, PDT, and gene therapy, intravenous injection of PPBP-siRNA + 808 nm and 660 nm laser irradiation significantly inhibited the growth and metastasis of tumor tissue after 42 days, with no side effects observed (Figure 20D). This simple and versatile therapeutic gene delivery strategy may open new avenues for personalized medicine.

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图20 （A）基于PPBP的平台的制备和siRNA递送的示意图；(B)不同处理组的HeLa细胞活力；(C)具有HeLa肿瘤的异种移植小鼠的热图像；(D)不同处理组的皮下HeLa异种移植物的肿瘤生长曲线^[135]

Fig. 20 (A) Schematic of the preparation and siRNA delivery of a PPBP-based platform; (B) HeLa cell viabilities for the different treatment groups; (C) Thermal images of xenograft mice with HeLa tumor; (D) Tumor growth curves of subcutaneous HeLa xenograft for the different treatment groups^[135]

4.2.2.3 Multi-Drug Co-Delivery Platform

Multidrug co-delivery systems have been developed as a new approach that significantly enhances the treatment of multidrug-resistant cancer. BP/polymer, with physiological stability and high specific surface area, provides the capability to effectively carry multiple drugs, thus can serve as a multimodal drug-loading therapeutic platform for cancer treatment.

Establishing a multifunctional drug delivery platform based on BP/PDA is a valuable strategy for simultaneously achieving BP stability and therapeutic efficacy. In 2018, Zeng et al^[136] used PDA-modified BPNSs to enhance the photothermal properties of BPNSs and conducted combined chemotherapy/gene/phototherapy on tumor cells. The delivery platform was prepared as follows: first, DOX and gene therapeutic agents (P-gp siRNA) were loaded onto the surface of BPNSs, followed by coating with a pH-responsive PDA membrane; finally, the surface was consecutively modified with dopamine (DA) (crosslinker) and NH₂-PEG-Apt (targeting agent) (Figure 21A). The thus-prepared nanocapsules exhibited excellent tumor-targeting capability, effectively transporting DOX and P-gp siRNA. After treatment with 808 nm NIR laser at pH=5.0, DOX release reached up to 46.9% due to PDA-induced pH and thermal responses, minimizing side effects and enhancing anti-tumor efficacy (Figure 21B). Following the injection of BPs@PDA-PEG-Apt, the temperature at the tumor site in mice rapidly increased to 54.7 ℃ within 5 minutes after NIR irradiation, leading to tumor death. The synergistic therapeutic effect of gene drugs, chemotherapeutic drugs, and NIR irradiation effectively inhibited multidrug-resistant breast cancer cells (Figure 21C).

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图21 （A）BP@PDA-PEG-Apt的制备和肿瘤细胞治疗；(B)体内红外热成像；(C)不同处理后肿瘤生长抑制曲线^[136]

Fig. 21 (A) Preparation and tumor cell therapy of BP@PDA-PEG-Apt; (B) In vivo IR thermal images; (C) Curves of the tumor growth inhibition after different treatments^[136]

4.2.3 Bone Regeneration

In clinical treatment, postoperative bone repair has always been an actual need to achieve ideal treatment outcomes^[137]. BP/polymer can be used to design and fabricate various bone regeneration biomaterials because phosphorus is an essential component of bone^[138-139]. In particular, BP can naturally degrade into non-toxic PO₄^3- in vivo, and the strong coordination between PO₄^3- and Ca²⁺ drives biomineralization.

Wang et al^[140] designed and fabricated a PLGA-based thermosensitive controlled-release platform for NIR-triggered bone repair, which was prepared by incorporating BPNPs and the bone growth-stimulating factor SrCl₂ into hydrophilic PLGA microspheres (BP-SrCl₂/PLGA) through an in-situ oil-in-water emulsion solvent evaporation strategy (Figure 22 A). Due to the formation of BP-SrCl₂/PLGA microspheres, the bioactive Sr²⁺ component could be rapidly and continuously released, and the microspheres were defective due to the high temperature generated under NIR irradiation. The effective mass concentration of Sr²⁺ was maintained within 10.72~18.94 μg/mL for an extended period, promoting bone regeneration, indicating precise release of Sr²⁺ into bone defects (Figure 22 B). In vitro experiments showed that near-infrared light could effectively degrade BP/PLGA microspheres into harmless small molecules CO₂, H₂O, and PO₄^2-. The microspheres exhibited excellent in vivo new bone regeneration ability under near-infrared irradiation. Subsequently, extensive osteogenesis similar to healthy bone was observed after 8 weeks. These BP/PLGA nanocomposites not only provide clinical potential for bone tissue regeneration but also can be extended to various therapeutic systems requiring precise control of drug release. Two other aspects can be comprehensively studied, namely whether BP can be stabilized by covalent interaction with Sr²⁺, and whether BP has the ability to promote bone regeneration alone (Figure 22 C). However, the excitation temperature should exceed 50 ℃, which will release bioactive Sr²⁺, potentially causing damage to surrounding normal tissues.

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图22 （A）BP-SrCl₂/PLGA制备和NIR光触发的骨再生的示意图；(B)BP-SrCl₂/ PLGA的释放和降解过程；(C)BP-SrCl₂/PLGA植入8周后骨再生的显微CT分析^[140]

Fig. 22 (A) Schematic of BP-SrCl₂/PLGA preparation and NIR-light-triggered bone regeneration; (B) Release and degradation processes of BP-SrCl₂/ PLGA; (C) Micro-CT analysis of bone regeneration following BP-SrCl₂/PLGA implantation after 8 weeks^[140]

Huang et al^[141] developed a novel strategy for bone regeneration via BP/polymer-based hydrogel scaffolds, which were prepared by encapsulating BP into gelatin methacrylamide (GelMA) and cationic gelatin-based unsaturated polyesteramide (PEA) hydrogels (BP/PEA/GelMA). The biocompatible BP/hydrogel captures Ca²⁺ through the sustained degradation of BPNSs into phosphate ions, accelerating biomineralization and bone regeneration at the bone defect site. After the introduction of BPNSs, the mechanical properties of the hydrogel were enhanced (Figure 23A). The BP/PEA/GelMA hydrogel scaffold exhibited a favorable degradation rate in vitro, matching the rate of new bone tissue formation. Notably, the BP/PEA/GelMA hydrogel demonstrated excellent photoresponsive release to enhance the osteogenic differentiation and mineralization properties of hDPSCs, providing PO_X^Y^- luciferin to capture Ca²⁺ under natural light illumination over 15 days. Bone regeneration was promoted via the bone morphogenetic protein 4 (BMP 4)-runt-related transcription factor 2 (RUNX 2) pathway (Figure 23B). After 12 weeks, new continuous bone structures containing many blood vessels and marrow cavities were formed at the bone defect sites in rabbit models implanted with BP-PEA/GelMA hydrogels (Figure 23C). Although photothermal studies were not discussed in this research, the strategy of forming a calcium-phosphate-free platform for bone defect site mineralization and bone regeneration still shows potential applications.

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图23 （A）捕获Ca²⁺以加速生物矿化和骨再生的BPNSs/水凝胶的构建；(B)用BP/PEA/GelMA水凝胶培养的hDPSCs的体外成骨分化的茜素红S染色图像；(C)颅骨模型中骨缺损的修复，植入12周后进行组织切片的H&E染色、碱性磷酸酶染色和免疫组织化学分析（BMP-2）^[141]

Fig. 23 (A) Construction of BPNSs/hydrogels capturing Ca²⁺ to accelerate biomineralization and bone regeneration; (B) Alizarin Red S staining images of the in vitro osteogenic differentiation of hDPSCs cultured with a BP/PEA/GelMA hydrogel; (C) Bone defect repair in the calvarial model. H&E staining, alkaline phosphatase staining and immunohistochemical analysis (BMP-2) of the histological sections were performed 12 weeks after implantation^[141]

Inspired by treatment strategies based on bone hyperplasia accelerating bone healing, Kumar et al^[142] fabricated a biodegradable bone implant based on BPNSs/PLGA membrane for near-infrared controlled bone regeneration. The membrane was prepared by in-situ exfoliation of BP and PLGA co-solvent (Figure 24 A). When the thickness decreased from 7 mm to 1 mm, under 808 nm laser irradiation (1.0 W/cm²), the temperature of the rat tibia implanted with BP@PLGA membrane (with a mass fraction of only 0.2% BPNSs) increased from 5.0 ℃ to 31.9 ℃, indicating the high PTCE of BPNSs/PLGA. PLGA can maintain the long-term bone growth stability of BPs within 8 weeks. Finally, BPNSs/PLGA membrane continuously degraded into harmless H₂O, CO₂, and PO₄^3- to accelerate bone reconstruction. Moreover, the mild photothermal effect generated by near-infrared radiation from the excited BPNSs/PLGA membrane is harmless to hBMSC cells. The combination of BPNSs/PLGA and NIR irradiation can effectively promote the expression of osteogenesis-related protein genes and contribute to significantly improving the osteogenic recovery of damaged bone cells in vitro (Figure 24 B). The temperature of the BPNSs/PLGA implanted at the injury site of the rat rapidly increased from 32.0 ℃ to (41.0±1.0) ℃ within 150 s, where NIR irradiation penetrated the tissue barrier. Meanwhile, new bone formation was observed at the injury site in vivo after 21 days of implantation without inflammation (Figure 24 C). The self-luminescent thermal ability of PLGA combined with BPs was confirmed by fluorescence labeling, micro-CT imaging, and Alizarin Red S staining, which could effectively promote in vivo osteogenesis after 10 weeks of implantation. Thermal stimulation of BP degradation into basic components that promote bone formation, namely PO₄^3-, can accelerate the disintegration of polymer fillers, making more space for osteogenesis. Overall, the implantation of polymer composite membranes stimulated by NIR light penetrating tissues generates a milder temperature (40~42 ℃) for thermotherapy, which is close to normal human body temperature (37 ℃) to induce in vivo bone injury repair. More notably, the presence of only NIR laser and BP can enhance the bone ingrowth of defective tibia through effective self-controlled thermotherapy (Figure 24 D). This "smart" bone implant with BPNSs/PLGA provides new research ideas for the remote control design of bone regenerative implants and shows good potential in cosmetic and plastic surgery applications.

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图24 （A）BPNSs/PLGA膜的制备过程；(B)用BPNSs/PLGA植入的大鼠胫骨的NIR刺激，示出注入和随后的NIR照射的进展的示意图；(C)近红外线照射下大鼠胫骨不同弯曲度的热像；(D)不同治疗组骨再生的MicroCT 3D重建^[142]

Fig. 24 (A) Preparation process of BPNSs/PLGA membranes; (B) NIR stimulation of rat tibia with BPNSs/PLGA implantation. Schematic diagram showing the progress of implantation and subsequent NIR irradiation; (C) Thermal images of rat tibia with different implantations under NIR irradiation; (D) MicroCT 3D reconstruction of bone regeneration for the different treatment groups^[142]

BP combined with polymers (e.g., PLGA, PEA, and GelMA) can be used to prepare various biocompatible and biodegradable nanocomposites for bone repair and regeneration, which is indeed a very good strategy. The excellent calcium ion capturing ability and photothermal conversion ability of BP are effectively highlighted and applied. BP-based polymer composites are a good therapeutic platform for osteosarcoma treatment and bone regeneration of damaged or post-surgical bones. In the future, further research on BP/polymer for bone repair can be conducted, such as how to generate neural and vascular systems during bone regeneration and muscle recovery near the damaged bone area.

4.2.4 Neurogenesis

The integration of nanomaterials and neuroscience has opened new avenues for providing neuroprotection in long-term clinical applications^[143-144]. Various liposomes, nanovesicles, and polymeric nanoparticles have been developed as nanomedicines to facilitate transcellular pathways across the blood-brain barrier (BBB)^[145-146]. BP nanosheets with photothermal effects and drug-loading properties can enhance the permeability of the BBB, making BP nanosheets a potential universal drug for treating neurodegenerative diseases. Typically, the presence of Cu²⁺ is considered a primary cause of neurodegenerative diseases (ND) because metabolic homeostasis abnormalities lead to protein aggregation and increased oxidative stress in nerve cells. Chen et al.^[147] prepared BPNSs with a thickness of 5.5 nm as effective neuroprotective nanomedicine. After near-infrared irradiation, BP can induce local thermal conversion, increasing the permeability of the blood-brain barrier. Most importantly, BPNSs act as antioxidants that can significantly reduce intracellular ROS production through Cu²⁺-catalyzed redox reactions, further decreasing Cu²⁺ concentration in ND treatment applications^[147].

Depression is one of the leading causes of suicide. However, existing treatments for depression often require several weeks or months to achieve an antidepressant effect. Therefore, there is an urgent need to improve treatment methods, shorten the onset time, and achieve low-toxicity antidepressant effects. In 2020, Jin et al^[148] designed and synthesized a BPNSs-based DDS containing the therapeutic drug fluoxetine (Flu), which successfully adsorbed onto the surface of BPNSs through electrostatic interactions. Antidepressant sample cells showed changes after two weeks of combined treatment including BP-Flu and NIR (808 nm irradiation), including increased expression of hippocampal brain-derived neurotrophic factor (BDNF), reduced excitability of amygdala projection neurons (PNs), and decreased frequency of miniature excitatory postsynaptic currents (mEPSCs), whereas treatment with free Flu alone for two weeks was ineffective. This suggests that the combination of BP-Flu and NIR may be a rapid and effective antidepressant strategy that can significantly reduce the treatment time for depression.

Electrical scaffolds based on multi-walled carbon nanotubes have been demonstrated to promote the differentiation and proliferation of PC12 cells in neuroblastoma cells^[149]. BP possesses biocompatibility and conductivity, which can contribute to nerve repair. In recent years, various synthetic and natural polymers with biocompatibility and conductivity, such as polycaprolactone (PCL), polylactic acid (PLA), PLCL, and PLGA, have been investigated and fabricated into nanofiber scaffolds for nerve tissue regeneration^[150⇓-152]. Surface chemistry, hydrophilicity, and morphology are key parameters in designing suitable electrospun scaffolds, which can influence initial cell adhesion and anchoring, subsequently affecting cell proliferation and viability on the scaffold^[153]. In 2019, Qian et al.^[154] were the first to report a biocompatible 3D BP/PCL composite nanoscaffold covered with a microporous structure to induce neurogenesis and promote angiogenesis under low oxidative stress for long-distance nerve defects prepared by layering. Figure 25A shows the results of bilayer bioassembly performed by repeatedly spraying a mixture of PCL and BP and microneedle dotting (Figure 25A). The BP/PCL nanomaterial is non-toxic to postoperative surrounding tissues due to its low c-caspase expression and slowly degrades into P_xO_y in an acidic environment six months after implantation. The material's long-term safety in vivo was confirmed by implanting it into the affected limbs of rats. Importantly, the nanoscaffold provides long-term mechanical stability to prevent nerve terminal entrapment and conduit collapse. By continuously releasing low concentrations of BP into the blood, the nanoscaffold effectively participates in immune regulation in vivo, including anti-inflammatory and antioxidant effects, promoting axonal regeneration and nerve myelin regeneration and repair. Additionally, it was preliminarily confirmed that this scaffold, with excellent electrical conductivity, can induce long-term axonal elongation and promote angiogenesis during tissue regeneration caused by lower ROS levels formed in blood vessels (Figure 25B). Composite scaffolds with BP nanosheets exhibit excellent ability to achieve nerve growth and regeneration due to their good electrical conductivity according to the level of GFAP expression in the brain. During angiogenesis, the gradually restored bioelectricity is transmitted to nerve branches and effectors through the composite scaffold. Moreover, the scaffold has protective and antioxidant effects around the injured peripheral nerves, promoting local neurite extension and microvessel formation. Finally, a 20 mm peripheral nerve defect was successfully regenerated through the BP nanoscaffold, responsively restoring immune homeostasis and angiogenesis in vivo. For BP nanoscaffolds, the mechanism of nerve injury repair involves activating the Ca²⁺ signaling pathway to upregulate the level of brain-derived neurotrophic factor in the nerve, thereby promoting axonal and myelin regeneration (Figure 25C). Meanwhile, the nanoscaffold promotes microvessel generation by regulating the proliferation and migration of endothelial cells. This report presents a novel perspective on using 3D scaffolds with BP nanosheets to repair long-distance nervous system defects for the first time. Further research can be conducted on the specific mechanisms of anti-inflammatory and bioelectrical effects induced by BP/polymer composites to promote their clinical application.

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图25 (A)用于神经发生的BP/PCL纳米支架的示意图；(B)基于BP的纳米支架的特性促进坐骨神经的体内再生；(C)BP/PCL纳米支架钙信号通路的研究^[154]

Fig. 25 (A) Schematics of BP/PCL nanoscaffold for neurogenesis; (B) Properties of BP-based nanoscaffolds promote the in vivo regeneration of sciatic nerves; (C) Investigation of the calcium signaling pathway of BP/PCL-based nanoscaffolds^[154]

4.2.5 Immunotherapy

Unlike surgery, radiotherapy, and chemotherapy, immunotherapy without any side effects is the most popular approach, where immune cells are stimulated to prolong anti-tumor effects and the cancer-fighting immune system is enhanced for tumor treatment. Nanomaterials, as the core of nanotechnology, are developing at an unprecedented speed in the field of immunology. BP nanomaterials with operable regulatory properties are suitable for integration with organic/polymer immunogens into nanocomposites for synergistic cancer immunotherapy. Photothermal or other responsive BP/polymer nanomaterials can enhance immunotherapeutic efficacy through rational modification of their composition, which accumulates in certain tissues to interact with tissue-resident DCs and T cells. Moreover, local hyperthermia can enhance the host's anti-tumor immune system response (CD₈⁺ T cells) to resist the recurrence and metastasis of cancer cells^[155].

4.2.6 Nano Prodrugs

Taking advantage of the unique properties of tumor cells being rich in hydrogen peroxide (H₂O₂) and glutathione (GSH), designing inorganic nano-prodrugs to in-situ generate damaging products at the tumor site for directly killing tumor cells is a method worth studying. Wu et al.^[156] first prepared a nano-prodrug based on BSA polymer and dextran conjugates for cancer treatment, which are coated on Te nanowires (TeNWs/BSA-dextran) with a width of 7 nm and a length of 82 nm, featuring a high aspect ratio for cancer therapy. The BSA-dextran conjugate plays an important role in enhancing the biocompatibility and long-term stability of TeNW/BSA-dextran in physiological media. Interestingly, TeNWs can effectively and selectively induce apoptosis in cancer cells without harming normal cells. TeNWs first react with intracellular H₂O₂ in cancer cells and produce toxic TeO₆^6- ions according to the following equation: Te + 3H₂O₂ ➞ 6H₆TeO₆, but this does not occur in normal cells. TeO₆^6- has strong cytotoxic effects that can lead to apoptosis. Telluric acid also reacts with GSH in cancer cells according to the following reaction formula: nGSH + TeO₆^6- ➞ GS-Te-GS + GSSG, which indirectly increases the level of antioxidant radicals and significantly improves the therapeutic effect on cancer cells. Clearly, TeNWs cause selective tumor cell death and apoptosis through DNA breaks in the nucleus and organic immune responses caused by high levels of H₂O₂. More importantly, TeNWs did not exhibit hepatotoxicity in vivo and can be completely cleared from the body. This novel H₂O₂-triggered BSA-dextran-coated TeNWs nano-prodrug provides new ideas for targeted cancer therapy to avoid side effects.

5 Conclusion and Prospect

In recent years, emerging BP/polymer nanomaterials and BPAs/polymer nanomaterials have experienced rapid growth and substantial progress in nanomedicine applications from fundamental research to next-generation technologies due to their unique advantages. The distinctive inherent properties of emerging BP and BPAs, such as large specific surface area, low cytotoxicity, tunable bandgap, and favorable PTCE, make them promising candidates in biomedicine, especially in cancer treatment. Various polymer modification strategies have been utilized not only to enhance desired physiological stability, stronger drug-loading capacity, excellent biocompatibility, tumor accumulation, and in vivo targeting of lesions but also to significantly reduce damage to normal tissues and organs, achieving significant synergistic processing results. This paper reviews the latest research progress of BP/polymer and BPAs/polymer nanomaterials in phototherapy, drug loading, bone regeneration, neurogenesis, and synergistic therapeutic systems. According to early studies, although BP/polymer and BPAs/polymer materials exhibit excellent performance showing potential applications for bare BP and BPAs, many issues still need attention, including future clinical research related to preparation, toxicity, and stability.

At present, there are still some defects in the preparation methods of BP and BPAs precursors, such as wide particle size distribution, intrinsic or extrinsic defects, low yield, and difficulties in practical applications, all of which are key factors affecting the direct efficacy of BP/polymer and BPAs/polymer in biomedical systems, thereby hindering their clinical translation. Moreover, the ultra-small size of BP and BPAs may influence drug release, tumor accumulation, penetration ability, retention in normal tissues, and excretion. Designing multifunctional therapeutic agents based on BP can provide a pathway for the development of nanomedicine. Additionally, although polymers have good protective properties for BP, their relatively poor thermal conductivity and light absorption capacity might reduce their ideal photothermal effect. Therefore, a theoretical model needs to be established to comprehensively study the interfacial interactions and synergistic effects between BP and polymers. Computational simulations combined with experimental properties can guide the selection and design of suitable polymers, including near-infrared light absorption depth and physiological protective effects in practical applications. Furthermore, biocompatible polymers with targeting and specific cell recognition capabilities can enhance tumor uptake and tumor homing, and provide better guidance for BP/polymer synthesis and functionalization, further enhancing their efficiency.

The potential long-term biosafety and biological effects remain the core challenge for the biomedical application of these polymer-modified black phosphorus and its analogous nanomaterials. Previous experiments and simulations have verified the high short-term biocompatibility and easy biodegradability of some BPAs/polymer composites. However, systematic evaluation of the in vivo acute toxicity and long-term chronic toxicity effects of these nanomaterials used in reproduction and neurology is very limited. In addition, there are few detailed studies on the in vivo metabolism of BPAs/polymeric materials. Moreover, almost all current assessments use mice as models which are not sufficient to reproduce the microenvironment of the patient's diseased area. Therefore, some large animal models such as rabbits or pigs need to be used to better understand the potential clinical possibilities.

Despite the fact that many issues and challenges involving nanomaterials need to be addressed for future clinical applications, BP/polymer and BPAs/polymer are still considered promising platforms for various therapeutic applications. In this context, these composite nanomaterials can be applied to more explorations of biomedical treatments such as antibacterial therapy and cardiac therapy, and even tissue engineering. Moreover, due to their excellent magneto-optical-electric properties, they can be used in smart sensing and wearable devices. Similarly, as an important direction of inorganic/organic hybrid materials, heterostructures/polymer can serve as another therapeutic agent in the biomedical field owing to their unique and superior performance.

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Outlines

模态框（Modal）标题

Abstract

Cite this article

1 Introduction

2 Preparation Method of BPNs

2.1 Mechanical Exfoliation

图1 BPN的金属辅助机械剥离[4]

2.2 Ultrasonic-Assisted Liquid Exfoliation Technique

2.3 Electrochemical Exfoliation

2.4 Chemical Vapor Deposition (CVD)

图3 通过CVD从RP粉末合成薄BP膜的装置[21]

2.5 Hydrothermal/Solvothermal Synthesis

图4 (A)使用溶剂热法合成BPN的程序[23]；(B)AFM；(C)SEM；(D)TEM

3 Structure and Properties of BPNs

3.1 Structure of BPNs

图5 BPNs的原子球杆模型:（A）3D表示；（B）顶视图；（C）侧视图[26]

3.2 Properties of BPNs

3.2.1 Direct and Tunable Bandgap

图6 (A)典型二维材料的电磁波谱和带隙范围[34]； (B)BPNs在降解过程中释放出对细胞无毒的PO43-和PO33-[43]；(C) BPNs的光诱导环境降解过程[46]

3.2.2 Electrical Conductivity

3.2.3 Biocompatibility

3.2.4 Instability

4 Biomedical Applications

4.1 Disease Diagnosis

4.1.1 Diagnostic Model Based on Low-dimensional BP

4.1.2 An Improved Feature-Based Diagnostic Model

4.2 Treatment Strategies

4.2.1 Phototherapy

4.2.1.1 PTT

图9 （A）BPQDs/PLGA NSs的制备和降解过程；(B)荷瘤小鼠近红外线照射后的红外热像图；（C）温度变化曲线；(D)BPQDs/PLGA NSs + NIR治疗后的肿瘤体积变化[109]

图10 （A) 纤维素/BPNSs水凝胶的合成；(B)不同给药组的体温变化；(C)不同组别治疗后肿瘤体积随时间的变化；(D)四组小鼠体重的变化[110]

4.2.1.2 PDT

图11 （A）PEG化BPQDs在PDT中的潜在应用的介绍[112]；(B)用PEG化BPQDs孵育后HeLa和L02细胞的浓度和细胞活力依赖性；(C)用DCFH-DA + PEG化BPQDs+光照射孵育的HeLa细胞的荧光显微镜图像；(D)不同处理后的肿瘤生长曲线

4.2.1.3 Combination of PTT and PDT

图12 （A）双功能Te NDs的制备；(B)近红外诱导Te NDs产生ROS的机制；(C)细胞内协同处理的示意图；(D)Te NDs的曲线可以产生活性氧；(E)不同治疗组小鼠的肿瘤体积变化[115]

图13 （A）用于癌症治疗的BPNSs@PEG/Ce6 NS制备和PDT/PTT的总结；(B)不同溶液组的温度变化；(C)不同组的体内光热效应；(D)不同组的体内抗肿瘤作用；(E)不同处理组的小鼠体重变化[116]

4.2.1.4 Combined PTT and Chemotherapy

图14 （A）Te NPs和PTW-Te NRs的制备和协同癌症治疗过程；(B)NIR照射下PTW-Te NPs溶液的温度；(C)不同细胞的IC50值；(D)不同治疗组肿瘤内注射的肿瘤部位的IR图；(E)不同治疗组的肿瘤体积[119]

4.2.1.5 Cooperative PTT and RT

图15 （A）PEG化Bi-LyP-1的制备和功能；(B)与不同治疗组联合后激光照射下小鼠的IR图谱；(C)不同治疗组的肿瘤体积曲线[124]

4.2.2 Drug Delivery Systems (DDSs)

4.2.2.1 Delivery of Chemotherapeutic Agents

图16 （A）作为药物递送平台的PEG化BP的示意图；(B)PEG化BP的DOX负载能力；(C)24 h后通过静脉内注射的PEG化BPNSs的体内NIR成像[129]

图17 （A）BP/DTX@PLGA NSs的制备和治疗过程的示意图；（B）和（C）注射BP/DTX@PLGA NSs后原发性肿瘤和肺转移性肿瘤的检测；(D)不同处理组的4T1-LG12细胞的细胞活力[131]

4.2.2.2 Delivery of Gene Reagents

图18 （A）制备新的功能性BPQDs@基于PAH的siRNA递送系统的示意图；(B)不同处理组PA-1细胞转染效率的流式细胞术评价；(C)不同处理组的PA-1细胞的相对细胞活力[133]

图19 （A）BPNSs-PEI-siRNA和协同PTT和基因疗法的制备过程的示意图；(B)用不同组处理后的细胞活力测定；(C)不同处理组的肿瘤生长曲线[134]

图20 （A）基于PPBP的平台的制备和siRNA递送的示意图；(B)不同处理组的HeLa细胞活力；(C)具有HeLa肿瘤的异种移植小鼠的热图像；(D)不同处理组的皮下HeLa异种移植物的肿瘤生长曲线[135]

4.2.2.3 Multi-Drug Co-Delivery Platform

图21 （A）BP@PDA-PEG-Apt的制备和肿瘤细胞治疗；(B)体内红外热成像；(C)不同处理后肿瘤生长抑制曲线[136]

4.2.3 Bone Regeneration

图22 （A）BP-SrCl2/PLGA制备和NIR光触发的骨再生的示意图；(B)BP-SrCl2/ PLGA的释放和降解过程；(C)BP-SrCl2/PLGA植入8周后骨再生的显微CT分析[140]

图24 （A）BPNSs/PLGA膜的制备过程；(B)用BPNSs/PLGA植入的大鼠胫骨的NIR刺激，示出注入和随后的NIR照射的进展的示意图；(C)近红外线照射下大鼠胫骨不同弯曲度的热像；(D)不同治疗组骨再生的MicroCT 3D重建[142]

4.2.4 Neurogenesis

图25 (A)用于神经发生的BP/PCL纳米支架的示意图；(B)基于BP的纳米支架的特性促进坐骨神经的体内再生；(C)BP/PCL纳米支架钙信号通路的研究[154]

4.2.5 Immunotherapy

4.2.6 Nano Prodrugs

5 Conclusion and Prospect

References

图1 BPN的金属辅助机械剥离^[4]

图3 通过CVD从RP粉末合成薄BP膜的装置^[21]

图4 (A)使用溶剂热法合成BPN的程序^[23]；(B)AFM；(C)SEM；(D)TEM

图5 BPNs的原子球杆模型:（A）3D表示；（B）顶视图；（C）侧视图^[26]

图6 (A)典型二维材料的电磁波谱和带隙范围^[34]； (B)BPNs在降解过程中释放出对细胞无毒的PO₄^3-和PO₃^3-^[43]；(C) BPNs的光诱导环境降解过程^[46]

图9 （A）BPQDs/PLGA NSs的制备和降解过程；(B)荷瘤小鼠近红外线照射后的红外热像图；（C）温度变化曲线；(D)BPQDs/PLGA NSs + NIR治疗后的肿瘤体积变化^[109]

图10 （A) 纤维素/BPNSs水凝胶的合成；(B)不同给药组的体温变化；(C)不同组别治疗后肿瘤体积随时间的变化；(D)四组小鼠体重的变化^[110]

图11 （A）PEG化BPQDs在PDT中的潜在应用的介绍^[112]；(B)用PEG化BPQDs孵育后HeLa和L02细胞的浓度和细胞活力依赖性；(C)用DCFH-DA + PEG化BPQDs+光照射孵育的HeLa细胞的荧光显微镜图像；(D)不同处理后的肿瘤生长曲线

图12 （A）双功能Te NDs的制备；(B)近红外诱导Te NDs产生ROS的机制；(C)细胞内协同处理的示意图；(D)Te NDs的曲线可以产生活性氧；(E)不同治疗组小鼠的肿瘤体积变化^[115]

图13 （A）用于癌症治疗的BPNSs@PEG/Ce6 NS制备和PDT/PTT的总结；(B)不同溶液组的温度变化；(C)不同组的体内光热效应；(D)不同组的体内抗肿瘤作用；(E)不同处理组的小鼠体重变化^[116]

图14 （A）Te NPs和PTW-Te NRs的制备和协同癌症治疗过程；(B)NIR照射下PTW-Te NPs溶液的温度；(C)不同细胞的IC50值；(D)不同治疗组肿瘤内注射的肿瘤部位的IR图；(E)不同治疗组的肿瘤体积^[119]

图15 （A）PEG化Bi-LyP-1的制备和功能；(B)与不同治疗组联合后激光照射下小鼠的IR图谱；(C)不同治疗组的肿瘤体积曲线^[124]

图16 （A）作为药物递送平台的PEG化BP的示意图；(B)PEG化BP的DOX负载能力；(C)24 h后通过静脉内注射的PEG化BPNSs的体内NIR成像^[129]

图17 （A）BP/DTX@PLGA NSs的制备和治疗过程的示意图；（B）和（C）注射BP/DTX@PLGA NSs后原发性肿瘤和肺转移性肿瘤的检测；(D)不同处理组的4T1-LG12细胞的细胞活力^[131]

图18 （A）制备新的功能性BPQDs@基于PAH的siRNA递送系统的示意图；(B)不同处理组PA-1细胞转染效率的流式细胞术评价；(C)不同处理组的PA-1细胞的相对细胞活力^[133]

图19 （A）BPNSs-PEI-siRNA和协同PTT和基因疗法的制备过程的示意图；(B)用不同组处理后的细胞活力测定；(C)不同处理组的肿瘤生长曲线^[134]

图20 （A）基于PPBP的平台的制备和siRNA递送的示意图；(B)不同处理组的HeLa细胞活力；(C)具有HeLa肿瘤的异种移植小鼠的热图像；(D)不同处理组的皮下HeLa异种移植物的肿瘤生长曲线^[135]

图21 （A）BP@PDA-PEG-Apt的制备和肿瘤细胞治疗；(B)体内红外热成像；(C)不同处理后肿瘤生长抑制曲线^[136]

图22 （A）BP-SrCl₂/PLGA制备和NIR光触发的骨再生的示意图；(B)BP-SrCl₂/ PLGA的释放和降解过程；(C)BP-SrCl₂/PLGA植入8周后骨再生的显微CT分析^[140]

图24 （A）BPNSs/PLGA膜的制备过程；(B)用BPNSs/PLGA植入的大鼠胫骨的NIR刺激，示出注入和随后的NIR照射的进展的示意图；(C)近红外线照射下大鼠胫骨不同弯曲度的热像；(D)不同治疗组骨再生的MicroCT 3D重建^[142]

图25 (A)用于神经发生的BP/PCL纳米支架的示意图；(B)基于BP的纳米支架的特性促进坐骨神经的体内再生；(C)BP/PCL纳米支架钙信号通路的研究^[154]