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Biopolymer-based bone scaffold for controlled Pt (IV) prodrug release and synergistic photothermal-chemotherapy and immunotherapy in osteosarcoma

Journal of Nanobiotechnology volume 23, Article number: 286 (2025) Cite this article

Abstract

Achieving bone defect repair while preventing tumor recurrence after osteosarcoma surgery has consistently posed a clinical challenge. Local treatment with 3D-printed scaffolds loaded with chemotherapeutic drugs can exert certain effects in tumor inhibition and bone regeneration. However, the non-specific activation of chemotherapeutic drugs leads to high local toxic side effects and the formation of an immunosuppressive tumor microenvironment, thereby limiting their clinical application and therapeutic efficacy. To address this, we designed a Pt (IV) prodrug with low toxicity and minimal side effects, which releases Pt (II) in response to glutathione. This prodrug was grafted onto polydopamine (PDA) through an amidation reaction, resulting in a composite nanomaterial (PDA@Pt) that possesses both photothermal synergistic chemotherapy and immuno-oncological properties. Subsequently, we innovatively employed selective laser sintering technology to incorporate PDA@Pt into a poly (L-lactic acid)/bioactive glass matrix, successfully constructing a composite scaffold with dual anti-tumor and bone repair capabilities. The study revealed that the composite scaffold significantly inhibited the growth of osteosarcoma cells and activated the cGAS-STING pathway by inducing DNA damage, ultimately converting the ‘cold tumor’ into a ‘hot tumor.’ Additionally, the composite scaffold could induce osteogenic differentiation of bone marrow mesenchymal stem cells and exhibited excellent bone repair capabilities in vivo.

Graphical abstract

Introduction

Osteosarcoma (OS) is the most common primary malignant bone tumor, characterized by poor prognosis, high recurrence rates, and low survival rates, posing a serious threat to the health of children and young adults [1, 2]. Although surgical resection combined with neoadjuvant chemotherapy is the current standard treatment [3, 4], the complex anatomical structures surrounding the tumor often hinder complete resection, increasing the risk of recurrence [5]. Moreover, systemic chemotherapy is frequently associated with severe side effects, inadequate local drug concentrations, and the development of drug resistance [6, 7]. Meanwhile, tumor heterogeneity and the immunosuppressive tumor microenvironment (TME) further compromise therapeutic efficacy [8]. Therefore, developing innovative strategies that integrate anti-tumor and bone repair functionalities to enhance treatment outcomes has become an urgent clinical challenge.

In recent years, the use of 3D-printed bone scaffolds for localized chemotherapy drug delivery has garnered significant attention in the comprehensive treatment of OS [9, 10]. These scaffolds effectively inhibit tumor growth by delivering high local drug concentrations while promoting bone regeneration to repair bone defects [11, 12, 13]. For example, Zeng et al. developed a bioactive CS/DOX@Ti-MOE scaffold, which demonstrated excellent local anti-tumor and bone repair efficacy while minimizing systemic side effects [14]. However, despite achieving tumor suppression at the implantation site, the high local doses of chemotherapeutic drugs often lead to toxic side effects. Additionally, the complex TME-characterized by increased acidity, overexpression of glutathione (GSH), and immunosuppression-further limits therapeutic efficacy [15, 16]. To address these challenges, the development of multimodal synergistic therapeutic platforms has become a research hotspot [17], aiming to enhance anti-tumor efficacy while minimizing side effects.

Studies have shown that the combination of chemotherapy with photothermal therapy (PTT) has proven to be highly effective in various cancer treatments [18, 19]. PTT, as a novel anti-tumor therapeutic strategy, offers advantages such as localized treatment, non-invasiveness, cost-effectiveness, and targeted control over the treatment area [20, 21, 22, 23]. Among the first-line drugs for OS treatment, platinum-based compounds stand out due to their high therapeutic index [24]. However, the clinical application and therapeutic efficacy of conventional divalent platinum drugs are limited by their strong toxicity and severe drug resistance [25]. Platinum (IV) (Pt (IV)) prodrugs have emerged as a promising solution due to their low toxicity, high efficacy, and reduced resistance [26, 27]. Pt (IV) prodrugs are intracellularly activated to release Pt (II), which induces DNA damage and activates the cGAS-STING signaling pathway, recruiting tumor antigen-specific T cells to infiltrate tumors, enhancing immune responses, and improving the TME [28, 29, 30]. Based on this, a multimodal synergistic therapeutic strategy combining Pt (IV) prodrugs with PTT provides a novel direction for post-surgical OS treatment.

This study developed a biodegradable 3D-printed bone scaffold platform for localized photothermal-chemotherapy, immune synergistic therapy, and bone repair in OS. First, a Pt (IV) prodrug with axial ligand modifications was designed by oxidizing Pt (II). This prodrug is activated by high GSH concentrations in the TME to release Pt (II), inducing DNA damage and activating the STING signaling pathway, thereby triggering anti-tumor immune responses. Second, Pt (IV) was grafted onto polydopamine (PDA), leveraging its photothermal conversion capabilities to achieve synergistic PTT and chemotherapy. Finally, using selective laser sintering (SLS), PDA@Pt composites were incorporated into a poly (L-lactic acid) (PLLA)/bioactive glass (BG) matrix to fabricate a bone scaffold with multimodal anti-tumor and bone repair functionalities. The physicochemical properties, on-demand drug release behavior, and photothermal effects of the scaffold were systematically characterized. Its anti-tumor efficacy and immune response were comprehensively evaluated in both in vitro and in vivo models. Additionally, the scaffold’s significant effects on bone regeneration were demonstrated through in vitro experiments on the osteogenic differentiation of bone marrow mesenchymal stem cells and in vivo cranial defect repair models Scheme. 1..

Scheme. 1
figure 1

A) Synthetic procedure of PLLA/BG/PDA@Pt composite bone scaffolds. B) The Mechanism of Photothermal Synergistic Chemotherapy and Immunotherapy in Treating OS Using Composite Bone Scaffolds. C) Schematic illustration of composite bone scaffold bone repair

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Results and discussion

Preparation and characterization of Pt (IV) prodrugs and PAD@Pt

The synthesis of Pt (IV) prodrugs is depicted in Fig. 1A [31]. Cisplatin was initially oxidized with hydrogen peroxide and then treated using succinic anhydride, a modifier that enables the axial ligand to retain the free carboxylic acid group. The Pt (IV) precursor prepared by this method demonstrated good reactivity and provided an effective binding site for stable attachment to biomolecules via amide bonds. The synthesized Pt (IV) prodrugs were characterized using nuclear magnetic resonance hydrogen spectroscopy (¹H-NMR), with deuterated dimethyl sulfoxide (DMSO-d₆) as the solvent (Fig. 1B). The peak (b) in the spectrum at a chemical shift of δ = 6.5 represented the amino hydrogen in the ligand amino group of the cisplatin parent, indicating that the product was a modified version of the cisplatin parent. Additionally, the peak (a) in the hydrogen spectrum at δ = 12.1 corresponded to the free carboxyl hydrogen in the target product. The cleavage peaks near δ = 2.3 (c ~ d) were indicative of the two methoxy groups in the target product. The successful preparation of the Pt (IV) precursor was verified by analyzing the chemical shifts and identifying the positions of the characteristic peaks [32]. Subsequently, the chemical valence states of the surface elements in the synthesized products were examined using X-ray photoelectron spectroscopy (XPS) (Fig. 1C). In the full-spectrum scan, the peaks at 75.43 eV of electron binding energy were attributed to the Pt4f characteristic line. Similarly, the peaks at 318.52 and 336.89 eV corresponded to the Pt4d characteristic line, and the peak at 198.99 eV corresponded to the Cl2p characteristic line. The peaks at 400.16 eV and 531.22 eV were associated with the N1s and O1s characteristic lines, respectively [33]. We further analyzed the Pt4f energy level (Fig. 1D). The proportions of Pt (IV) and Pt (II) were 72.45% and 27.55%, respectively, based on the fitted peak areas. These findings confirmed the successful preparation of the Pt (IV) precursor.

PDA was synthesized through in situ self-polymerization of dopamine [34]. Subsequently, PDA@Pt was created by grafting Pt (IV) onto PDA. The morphology and structure of PDA and PDA@Pt were analyzed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). As demonstrated in Figure S1, PDA exhibited a uniform spherical morphology. After incorporating Pt (IV), PDA@Pt maintained its spherical shape, though its edges appeared slightly rough at higher magnification (Figure E, F, and G). The elemental distribution of PDA@Pt was further examined using energy-dispersive spectroscopy (EDS) (Fig. 1H, I). We observed that the elements Pt, Cl, N, and O were uniformly present in the samples, indicating the successful grafting of Pt onto PDA. Additionally, the size of PDA@Pt nanoparticles was investigated using dynamic light scattering (DLS). The results (Figure J) showed that the average particle size of PDA@Pt was approximately 226.52 nm. To further explore the synthesis mechanism of PDA@Pt, we performed Fourier transform infrared spectroscopy (FTIR) analysis on PDA and PDA@Pt. As shown in Fig. 1K, the appearance of the amide I band and the amide III band in the PDA@Pt spectrum indicated that Pt (IV) was grafted onto PDA through an amidation reaction, confirming the successful synthesis of PDA@Pt [35, 36, 37].

Fig. 1
figure 1

A) Synthesis of Pt (IV) prodrugs and PDA @ Pt. B) 1H-NMR spectrum of Pt (IV) prodrugs. C)XPS spectra of Pt (IV) prodrugs. D) Pt4f peak fitting spectrum. E, F, and G) TEM image of PDA@Pt. H) Elemental mapping images (C, O, N, and Pt elements) of PDA@Pt. I) EDS profile confirming the presence of C, O, N, and Pt elements in PDA@Pt. J) Size distribution of PDA@Pt. K) FTIR spectrum of PDA and PDA@Pt

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Preparation and characterization of the bone scaffolds

The preparation process for bone scaffolds is shown in Fig. 2A. Specifically, BG, PDA, and PDA@Pt were introduced into the PLLA, respectively. The bone scaffolds were fabricated by SLS [38]. The prepared PLLA, PLLA/BG, PLLA/BG/PDA, and PLLA/BG/PDA@Pt bone scaffolds were named PLLA, PB, PBP, and PBPPt, respectively. These 3D-printed scaffolds exhibited interlocking, uniformly interconnected porous structures with an average pore size of approximately 420 ± 28 μm (Figure S2). Studies have indicated that such multi-channel structured bone scaffolds can induce new bone tissue to grow along these channels, thereby enhancing the integration between the scaffold and the surrounding native bone [39]. This design achieves a balance between mechanical performance and biocompatibility, making it highly suitable for bone tissue engineering applications [40, 41]. The physical phase composition of the bone scaffold was characterized by X-ray diffraction (XRD). The results showed the presence of diffraction peaks associated with PLLA, BG, and Pt on the PBPPt bone scaffold (Fig. 2B). The diffraction peaks of PLLA were located at (110) / (220) [42]. The peaks of BG were at (002) and (211) [43], while those of Pt were at (111) and (200) [44]. XPS analysis indicates the enrichment of Pt within the PBPPt scaffold (Fig. 2C). The morphology and elemental distribution of the bone scaffolds were comprehensively studied using SEM and EDS. As shown in Figures S3A and S3B, both PB and PBPPt scaffolds exhibited rough, porous microstructures. These microstructures significantly enhance the surface activity of the scaffolds, promoting cell adhesion, proliferation, and differentiation [45]. High-magnification SEM observations further revealed the uniform distribution of PDA@Pt on the PBPPt scaffold surface (Figures S3D and S3E). Additionally, EDS analysis confirmed the uniform distribution of Si, Ca, P, N, Cl, and Pt elements on the PBPPt scaffold surface (Fig. 2D and E). Furthermore, Figures S3C and S3F validated the successful fabrication of the PB scaffold. Collectively, these results confirm the successful fabrication of the PB and PBPPt bone scaffolds and highlight their superior structural characteristics.

Fig. 2
figure 2

A) Preparation flow chart of bone scaffolds. B) XRD spectra of PB and PBPPt bone scaffolds. C) XPS spectra of PBPPt bone scaffolds. D, E) EDS spectrum of PBPPt bone scaffolds

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Evaluation of the mechanical properties of bone scaffolds

In bone tissue engineering, bone scaffolds must possess sufficient mechanical strength to withstand in vivo pressure [46]. Studies have shown that newly designed scaffolds often utilize finite element analysis (FEA) to simulate mechanical performance and optimize their internal and external structures [47]. However, the porous structure, gradient design, and drug loading of the composite scaffolds in this study introduced additional complexity to simulations. Therefore, we directly measured the mechanical properties of the scaffolds using a universal testing machine (Fig. 3A). Compression specimens were first prepared for compression tests, and the results showed that the compressive strength and modulus of the scaffolds were significantly enhanced with the introduction of BG and PDA@Pt, as shown in Fig. 3D. Specifically, the compressive strength and modulus of PLLA scaffolds were only 15.53 ± 0.62 MPa and 0.59 ± 0.23 GPa, respectively, while the compressive strength and modulus of PBPPt increased to 28.40 ± 0.48 MPa and 0.8 ± 0.02 GPa, respectively, which is comparable to those of cancellous bone [48]. This improvement may be attributed to the increase in polymer density and stress transfer effect due to the doping of BG as a rigid reinforcing phase, as well as the role of PDA as a plasticizer, which increases the mobility of PLLA molecular chains and synergistically improves the crystallinity of PLLA [49, 50]. Similarly, a comparable effect was observed for tensile strength and strain, as shown in Fig. 3E.

Evaluation of the hydrophilicity and mineralization of bone scaffolds

In general, hydrophilic scaffolds are more favorable for cell adhesion. Therefore, the hydrophilicity of PLLA, PB, and PBPPt scaffolds was investigated using a water contact angle test. As shown in Fig. 3F, the contact angle of the PLLA scaffolds was 103.53 ± 3.4°. The water contact angle decreased, and the hydrophilicity of the scaffolds increased with the addition of BG and PDA@Pt. The PBPPt scaffold showed the best hydrophilicity, with a water contact angle of 76.53 ± 2.08°. The improved hydrophilicity of the scaffold may be attributed to the inherent hydrophilicity of BG and the presence of hydroxyl and amide groups on PDA surfaces [51, 52, 53]. In vitro biomineralization studies are an effective way to evaluate the bioactivity of biomaterials [54], and previous studies have shown that BG scaffolds exhibit good in vitro bioactivity [55]. The ability to form an apatite layer on the scaffold was evaluated by immersing bone scaffolds in SBF solution at 37 °C for 28 days. The morphology and Ca/P ratio of PLLA, PB, and PBPPt scaffolds were investigated using SEM. As shown in Fig. 3B, C, and S4, numerous spherical precipitates were deposited on the surface of PB and PBPPt scaffolds, whereas PLLA scaffolds exhibited surfaces with only a few precipitates. This may be attributed to the good in vitro bioactivity of BG and the bioinert nature of PLLA. Furthermore, more spherical precipitates were observed on PBPPt scaffolds than on PB scaffolds. The elemental composition of the spherical precipitates was confirmed by EDS. The Ca/P ratio of the PBPPt bone scaffold deposition layer increased from 1.61 to 1.64 after the introduction of PDA. This could be attributed to the abundant catechol groups in PDA, which promoted the chelation of calcium ions, facilitating the formation of the apatite layer [56, 57]. Overall, PBPPt bone scaffolds exhibited better bioactivity, laying the foundation for for their bone-enhancing role [58].

In vitro photothermal effect of bone scaffolds

Based on the strong near-infrared (NIR) absorbance and photothermal conversion ability of PDA [59, 60], we measured the UV-Vis-NIR absorption spectra of PDA and PDA@Pt nanoparticles. The results revealed significant absorption in the wavelength range of 650–900 nm (Figure S5). To further evaluate the photothermal performance, we studied the temperature changes of the bone scaffolds under 808 nm NIR irradiation. First, we evaluated the photothermal performance of bone scaffolds loaded with different concentrations of PDA. As shown in Figure S6, as the PDA content in the scaffold increased, the maximum temperature of the solution within 10 min rose from 35 °C to 60 °C. Subsequently, we assessed the photothermal performance of bone scaffolds containing different loading concentrations of PDA@Pt (0, 1.0, 1.5, and 2.0 wt%) under different power densities (0.5, 1.0, and 1.5 W/cm²) of NIR laser irradiation. The temperature of the pure PB scaffold solution did not increase significantly (Figure S7), indicating the absence of photothermal conversion properties. In contrast, the temperature changes of PBPPt bone scaffolds in solution were dependent on both concentration and laser power density (Fig. 3G, H), indicating the excellent photothermal conversion ability of PBPPt bone scaffolds. Additionally, the maximum temperature of the PBPPt bone scaffolds did not decrease significantly over five NIR cycles (Fig. 3I), demonstrating their excellent photothermal stability.

Evaluation of Pt release and reduction response of bone scaffold

Studies have shown that Pt (IV) prodrugs are usually less toxic and exert anti-tumor effects primarily through their reduction to the highly cytotoxic Pt (II) by GSH, which is highly expressed in tumor cells [61]. Additionally, the breakdown of carbamoylurea bonds facilitates the release of Pt (II) [35]. To investigate this mechanism, we investigated the reduction-responsive properties of PBPPt bone scaffolds in vitro by simulating a tumor-reducing physiological environment (10 mM GSH, pH 6.5). The valence distribution of the Pt element was characterized by XPS, revealing that Pt in the composite bone scaffolds was primarily in the divalent form (Fig. 3J). The split-peak fitting of the Pt4f energy levels was performed using XPS PEAK, estimating that the Pt (IV) component was 37% and the Pt (II) component was 63%, based on the area calculation of the fitted peaks (Fig. 3K). These results indicated that Pt (IV) in PBPPt bone scaffolds exhibited good reduction-responsive properties under the reducing physiological conditions of tumor cells. To evaluate the local release properties of Pt, we immersed PBPPt bone scaffolds in PBS solution under different temperature conditions (37 °C and 48 °C). As shown in Fig. 3L, the scaffolds exhibited a faster release rate during the initial immersion phase, with a cumulative Pt release concentration of 0.242 µM on day 1. After 14 days, the release rate stabilized, reaching a cumulative concentration of 2.205 µM. Additionally, increasing the local temperature significantly accelerated Pt release, likely due to enhanced drug diffusion at higher temperatures [62, 63]. This finding suggests that local Pt release can be effectively controlled by adjusting NIR irradiation to regulate the local temperature. Overall, based on the strong reduction response and photothermal synergy, we found that PBPPt bone scaffolds can deliver chemotherapeutic drugs locally in synergy with PTT anti-tumor therapy. This approach can maximize therapeutic efficacy while reducing the drug’s side effects.

Fig. 3
figure 3

A) Images of the scaffold before and after the tensile test. B, C) The SEM and EDS images of the PB and PBPPt composite scaffolds Upon submerging in SBF for a duration of 28 days. D) compressive strength and modulus of the bone scaffolds. E) tensile strength and modulus of the bone scaffolds. F) Water contact angles of the bone scaffolds. G) Temperature increase profiles of PBPPt scaffolds with varying PDA@Pt contents (1.0%, 1.5%, and 2.0%) and PB scaffolds under 1.0 W/cm² irradiation for 10 min. H) Temperature increase of the 1.5%PBPPt under NIR irradiation of 0.5, 1.0, and 1.5 W/cm2 during 10 min. I) Temperature changes of the 1.5% PBPPt during five on/off cycles of NIR irradiation at 1.0 W/cm2 for 50 min. J, K) Valence transformation of Pt (IV) prodrugs in bone scaffold under tumor physiological condition in vitro (XPS characterization). L) Cumulative Pt release from PBPPt scaffolds under varying temperature conditions

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In vitro anti-tumor performance evaluation of bone scaffolds

Based on the outstanding performance of our bone scaffold, we further investigated the anti-tumor effects of the scaffolds at the cellular level. First, the in vitro cytotoxicity and anti-tumor performance of the bone scaffolds were evaluated using the standard Cell Counting Kit-8 (CCK-8) assay. HOS cells were co-incubated with PB, PBP, and PBPPt bone scaffolds, with or without laser irradiation (808 nm, 1.0 W/cm²) for 10 min. As shown in Fig. 4B, the percentage of viable cells in the PB, PB + NIR, and PBP groups ranged between approximately 90–100%, with no significant differences observed, indicating that the prepared PB and PBP bone scaffolds exhibit good biocompatibility. In contrast, cell viability was reduced in the PBP + NIR and PBPPt groups. Among these, the PBPPt + NIR group exhibited the lowest cell viability, revealing the strongest tumor-killing ability of the PBPPt scaffolds, which produced a synergistic anti-tumor effect through the combination of chemotherapeutic agents and PTT. Additionally, interconnected macroporous structures fabricated by 3D printing technology, as well as live/dead cells adhering to ordered square bar scaffolds, were visualized by confocal laser scanning microscopy (CLSM). The dead and living cells on the scaffolds were stained with propidium iodide (PI, red) and calcein-AM (green), respectively (Fig. 4A). The results indicated that both the PBP + NIR and PBPPt groups exhibited varying degrees of ability to induce HOS cell death, with the PBPPt + NIR group demonstrating the strongest anti-tumor effect. The quantitative results of live/dead cell staining were consistent with the CCK8 results (Fig. 4C). Similarly, the potent anti-tumor efficacy of the PBPPt + NIR group was also confirmed in K7M2 cells (Figures S8, S9).

Furthermore, studies have indicated that the primary mechanism by which anti-tumor drugs induce cell death is through apoptosis [64]. Flow cytometry (FCM) analysis using Annexin V-PI double staining was conducted to assess apoptosis in each group. As shown in Fig. 4D and F, the induction of apoptosis in the PB group was negligible. In contrast, the apoptosis rate increased in the PBP + NIR and PBPPt groups, while the apoptosis rate in the PBPPt + NIR group was significantly higher than in the other groups, with the distribution of the cell population predominantly shifting to the late apoptosis quadrant. Additionally, studies have shown that the generation of reactive oxygen species (ROS) is also an important factor in the anti-tumor effects of platinum-based drugs [65]. We measured intracellular ROS levels using the ROS-specific fluorescent probe 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA). As shown in Fig. 4E and S10, compared to the PB and PBP + NIR groups, the PBPPt group exhibited a certain degree of increased ROS levels, while the fluorescence intensity in the PBPPt + NIR group was significantly higher. These results suggest that under NIR irradiation, the induction of oxidative stress by PBPPt is accelerated. In summary, both the PBP + NIR and PBPPt groups demonstrated anti-tumor effects, attributed to the photothermal effects of the scaffold and the on-demand release of highly toxic Pt (II) in response to high GSH levels in the TME to kill tumor cells. The PBPPt group showed the strongest anti-tumor capability, which can be attributed to PTT-induced heating that enhances the sensitivity of tumor cells to chemotherapy [66, 67], thereby achieving a synergistic anti-tumor effect between PTT and chemotherapeutic drugs.

Fig. 4
figure 4

A) CLSM images of HOS cells on bone scaffold treated with or without NIR irradiation with further staining with Calcein-AM/PI. B) quantification for live and dead cells. C) Viability of HOS cells treated with different conditions. D, F) Cellular apoptosis profiles of HOS cells on bone scaffolds after various treatments and apoptosis rate. E) Intracellular ·OH was detected in HOS cells cultured on scaffolds using DCFH-DA. (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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The scaffold induces DNA damage and activates the cGAS/STING pathway in vitro

To further investigate the mechanism by which the bone scaffold induces tumor cell death and its immune effects, we conducted experiments using K7M2 cells. Extensive research has shown that DNA is a recognized target of platinum-based anti-tumor drugs, and platinum-induced apoptosis is associated with DNA double-strand breaks [68, 69]. Therefore, we used the phosphorylated histone variant (γ-H2AX) as a marker for DNA double-strand breaks and evaluated the effect of the bone scaffold in inducing enhanced DNA damage using immunofluorescence. As shown in Fig. 5A, compared to the control group, weak fluorescent signals of damaged foci were observed in the PBP + NIR and PBPPt groups, likely associated with the early apoptosis induced by PTT treatment and Pt (II). In the PBPPt + NIR group, a stronger fluorescent signal was observed compared to the other groups, along with nuclear shrinkage, which can be attributed to the synergistic DNA damage in OS cells caused by the combined effects of PTT treatment and Pt (II). Research has shown that double-stranded DNA (dsDNA) fragments generated from DNA damage can enter the cytoplasm, where they are recognized by cGAS [70, 71, 72]. cGAMP can activate STING and prompt its relocation from the endoplasmic reticulum to the Golgi apparatus, thereby mediating the release of a series of pro-inflammatory cytokines, activating innate anti-tumor immunity, and converting ‘cold tumors’ into ‘hot tumors’ (Fig. 5B) [73, 74, 75]. To investigate the ability of the scaffold-released Pt to activate the cGAS-STING pathway in OS cells (K7M2), immunofluorescence staining for p-STING (red) and dsDNA (green) was performed on K7M2 cells from different treatment groups. CLSM results showed that the red and green fluorescence intensities in K7M2 cells treated with PBPPt + NIR were significantly higher than in those treated with PBP + NIR or PBPPt alone (Fig. 5C, D). Subsequently, semi-quantitative analysis of p-STING protein in K7M2 cells was conducted using ImageJ software. The results indicated that the intracellular red fluorescence intensity in K7M2 cells treated with PBPPt + NIR was significantly higher than in the other groups (Figure S11). Additionally, we further validated the activation of the STING pathway using Western Blot (WB) analysis. Proteins were extracted from K7M2 cells treated with different scaffolds, and the expression levels of proteins related to the STING pathway were analyzed by WB. The results showed that the PBPPt + NIR group significantly increased the phosphorylation levels of p-STING, p-IRF3, and p-TBK1 in tumor cells (Fig. 5E, F, S12), which is consistent with the immunofluorescence results. These findings suggest that the PBPPt scaffold, under the influence of PTT, significantly increased the accumulation of cytoplasmic dsDNA and activated the cGAS/STING pathway by releasing highly toxic Pt (II).

It is well-known that dendritic cells (DCs) play a crucial role in initiating and regulating immune responses [76]. To further assess the effect of the bone scaffold in inducing immune responses through the cGAS-STING pathway, we extracted bone marrow DCs from mice and co-cultured them with K7M2 cells treated with different scaffold groups for 24 h. First, the levels of IFN-β, IL-10, and CXCL10 in the co-culture system were measured using enzyme-linked immunosorbent assay (ELISA). The results showed that the levels of IFN-β, IL-10, and CXCL10 in the culture medium of mice treated with PBPPt + NIR were significantly higher than those in the other groups (Figure S13). Additionally, we further examined the surface markers of DCs using FCM. The results indicated that the percentage of mature DCs was highest (45.3%) after co-incubation with K7M2 cells treated with PBPPt + NIR, which was significantly higher than in cells treated with PBP + NIR (approximately 22.2%) and PBPPt (approximately 25.1%) (Fig. 5G, H). This suggests that K7M2 cells treated with PBPPt + NIR promote DCs maturation. In conclusion, PBPPt + NIR effectively induces intracellular DNA damage, activates the cGAS-STING pathway, and promotes DCs maturation, thereby initiating and activating tumor antigen-specific T-cell infiltration into the tumor.

Fig. 5
figure 5

A) Fluorescence images of the DNA double-strand break marker γ-H2AX. B) Schematic illustration of Pt causing DNA damage and activating the cGAS-STING pathway (Created with BioRender.com). C) Representative Fluorescence images of p-STING (red) in K7M2. D) Representative Fluorescence images of dsDNA (green) in K7M2. E) Western blot analysis was used to the STING pathway, and β-actin was used as an internal reference protein. F) quantification analysis of p-STING expression. G) The percentages of mature DC (CD80+ CD86+) populations in each group presented as histograms. H) Flow cytometric assessment images for DCs activation cocultured with K7M2 cells treated with scaffold. (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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Assessment of in vivo anti-tumor performance

Based on the excellent anti-tumor performance of the composite bone scaffold in vitro, further evaluation of its therapeutic efficacy in vivo was conducted by establishing an OS xenograft model [77]. Briefly, a subcutaneous OS model was established in Balb/c nude mice. When the tumor volume reached approximately 100 mm³, PB, PBP, and PBPPt scaffolds were implanted in situ at the tumor’s center. This was followed by NIR irradiation (808 nm, 1 W/cm²), and in situ thermal images were recorded by an infrared camera (Fig. 6A). In the PBPPt scaffold group, the tumor tissue temperature rapidly increased from 30 °C to 50 °C, while no significant temperature increase was observed in the PB scaffold-alone group (Fig. 6B). Two weeks after treatment, the biocompatibility of the composite scaffold in vivo was evaluated by monitoring the body weight of Balb/c nude mice. As shown in Fig. 6C, the body weight fluctuations of all mice were negligible, confirming that the treatments had no significant adverse effects on the health of the mice. Based on the monitoring of tumor volume, weight, and corresponding local tumor images in Balb/c nude mice from different treatment groups (Fig. 6D, E, F), we observed that the tumors in the PB scaffold group continued to grow without any therapeutic effect. In contrast, limited tumor inhibition was observed in the PBP + NIR and PBPPt groups. Notably, the tumor inhibition effect was more pronounced in the PBPPt + NIR group. Additionally, we assessed tumor tissue necrosis through H&E, TUNEL, and Ki67 staining. As shown in Fig. 6G, tumor cells treated with PBP + NIR and PBPPt exhibited varying degrees of apoptosis and necrosis. Notably, the PBPPt + NIR group showed the most pronounced nuclear condensation and fragmentation (H&E images) and the highest level of apoptosis (TUNEL images) compared to the other three groups. Furthermore, the expression of Ki67 was significantly reduced in the tumor tissues of the PBPPt + NIR group. H&E staining of major organs (heart, liver, spleen, lungs, kidneys) in Balb/c nude mice showed no significant morphological changes across the different treatment groups (Figure S14). These findings suggest that the chemophotothermal therapy synergism of the PBPPt bone scaffold effectively kills OS cells while causing no significant damage or toxicity to the major organs and tissues of Balb/c nude mice. Therefore, this 3D-printed composite bone scaffold, developed in this study, may serve as a potential post-surgical treatment implant for OS due to its excellent biocompatibility and therapeutic performance.

Fig. 6
figure 6

A) Infrared thermographic photographs of the tumor-bearing nude mice post-implanted with PB and PBPPt scaffolds and subsequently irradiated by 808 nm laser (1 W/cm2) for different time intervals with the color bar referring to the relative temperature. B) Real-time temperature increases in OS tissue corresponding to (A). C) Time-dependent body weight curves of nude mice after different treatments. D) Time-dependent tumor-growth curves of the mice after different treatments. E) Tumor weight size after different treatments in nude mice F) Photographs of osteosarcoma-bearing nude mice after different treatments on day 14. G) H&E, TUNEL and Ki67 staining of tumor slices. (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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Evaluation of immune response activation by the bone scaffold in vivo

In vitro experiments demonstrated that, under the synergistic effect of PTT, the accelerated release of Pt from the PBPPt scaffold effectively induced intracellular DNA damage, activated the cGAS-STING pathway, and mediated the production of interferons and other pro-inflammatory factors. This process reprograms TME into an immune-promoting phenotype, ultimately enhancing the anti-tumor immunogenic effect. To further investigate this, we first established a subcutaneous OS model in Balb/c mice. When the tumor volume reached approximately 100 mm³, PB, PBP, and PBPPt scaffolds were implanted in situ at the tumor center, followed by NIR intervention (Fig. 7A). After NIR irradiation (808 nm, 1 W/cm²), thermal imaging and heating curve results showed that the temperature in the tumor tissue of the Balb/c mice in the PBPPt scaffold group rapidly increased to 49.8 °C, while the temperature in the PB scaffold group did not show a significant rise (Figure S15). As expected, the tumor images taken two weeks after treatment (Fig. 7B) and the tumor growth inhibition curves (Fig. 7C) showed that the PBPPt + NIR group exhibited the strongest tumor inhibition effect, indicating a significant synergistic effect of PTT combined with chemotherapy and immunotherapy. Survival analysis of the mice was conducted, as shown in Figure S16. During the observation period, the median survival time of mice in the PB group was relatively short. In contrast, the median survival times in the PBP and PBPPt treatment groups were extended, with the PBPPt + NIR group showing a significantly prolonged survival, further confirming the superior therapeutic effect of PBPPt + NIR. Additionally, the body weight fluctuations of all mice were negligible (Fig. 7D), confirming that the treatments had no significant adverse effects on the health of the mice. These results further demonstrate that the PBPPt scaffold under PTT exhibits significant anti-tumor activity and good biosafety in Balb/c mice.

To further explore the immune response in the tumor microenvironment (TME) following different treatments, we performed immunohistochemical staining for STING protein in tumor tissues. As shown in Fig. 7E, the expression of STING protein was significantly elevated in the PBPPt + NIR group, indicating that the PBPPt scaffold can activate the STING pathway in vivo under PTT. It is well-known that CD8 T cells release granzyme, a serine protease, which can kill tumor cells. To detect the infiltration of CD8 T cells in the tumors, immunofluorescence staining was performed on tumor sections using CD8 and granzyme B (GZMB) antibodies. The results showed that the expression of both CD8 and GZMB was significantly enhanced in the tumor tissues of mice treated with the PBPPt + NIR group (Fig. 7F, G and S17). Taken together, these findings suggest that the immune response within the Balb/c mouse model is induced by the activation of the cGAS-STING pathway. Research indicates that immunogenic effects can be diminished by the immunosuppressive microenvironment, which is regulated by regulatory T cells (Tregs) [78]. Therefore, we further investigated the primary regulatory factor of Tregs, Foxp3. As shown in Fig. 7H, the fluorescence intensity of Foxp3 was significantly reduced in the PBPPt + NIR group, indicating that Treg generation was inhibited under the PBPPt + NIR intervention, ultimately enhancing the immune response within the animal model. DCs, as the most potent antigen-presenting cells in the body, play a crucial role in anti-tumor immunity. To this end, we further analyzed the maturation of DCs in vivo using FCM. The results showed that the proportion of mature DCs (CD80, CD86) in the tumor tissues of mice treated with PBPPt + NIR was significantly higher than in the PBP + NIR and PBPPt groups (Fig. 7K, S18). This indicates that the PBPPt scaffold promotes DCs maturation in vivo under PTT. Subsequently, we examined the changes in cytokine levels (IL-10, TNF-α, and IFN-γ) in the tumors using ELISA. The results showed that cytokine levels were elevated in the tumor tissues of the PBPPt + NIR group (Fig. 7L, I and J). In conclusion, the PBPPt scaffold induces DNA damage through the synergistic effects of photothermal therapy and chemotherapy, leading to apoptosis or necrosis of cancer cells while releasing a substantial amount of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) [79, 80]. Studies have shown that the functional groups in the bone scaffold, derived from PDA and PLLA (amine, carboxyl, and hydroxyl groups), efficiently capture antigen molecules and prolong their retention time, thereby providing sustained immune stimulation [81, 82, 83]. The captured antigens further promote the maturation of DCs, activate CD4⁺ and CD8⁺ T cells, and simultaneously inhibit the generation of Tregs. This process enhances the levels of pro-inflammatory cytokines within the tumor, ultimately transforming the ‘immune cold tumor’ into an ‘immune hot tumor.’

Fig. 7
figure 7

A) Schematic illustration of treatment schedule (Created with BioRender.com). B) Photograph of tumors extracted from mice with different treatments on day 14. C) tumor growth inhibition curves and D) Body weight changes after various treatments. E) Expression of STING in tumors by immunohistochemistry. (F) Immunofluorescence staining of CD8 and G) Granzyme B in tumor tissues. (H) Immunofluorescence staining of Foxp3 in tumor tissues. L, I, J) The levels of IFN-γ, TNF-α, and IL-10 in the tumors were quantified by ELISA, respectively. (K) Flow cytometric examination of DCs maturation in vivo after various treatments. (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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In vitro osteogenic performance evaluation of bone scaffolds

Notably, BG and PDA have good biocompatibility and osteogenic properties [84, 85]. Therefore, we investigated the in vitro cell attachment, cell proliferation, and osteogenic properties of rat bone mesenchymal stem cells (rBMSCs) on composite bone scaffolds (Fig. 8A). The cytotoxicity and cell proliferation of the bone scaffolds were assessed using the CCK8 assay (Fig. 8B and C). The results showed that the cells on the scaffolds maintained good viability after 1, 4, and 7 days of incubation. All scaffolds promoted cell proliferation over time, indicating excellent cytocompatibility across all groups. The cell morphology and attachment of rBMSCs on the scaffold surfaces in each group were observed using CLSM, as shown in Fig. 8D. The results demonstrated that with prolonged cultivation time, rBMSCs continuously proliferated on the surfaces of all scaffold groups. Notably, the PBPPt group exhibited cells with a polygonal bone-like morphology, accompanied by abundant filamentous pseudopodia structures. The morphologies of rBMSCs on PBPPt scaffolds were also observed by SEM, and the results were consistent with those from the CLSM assays. These findings suggest that the composite bone scaffolds support rBMSC adhesion and promote cell proliferation with good biocompatibility and bioactivity (Fig. 8E). Given the significant role of numerous filamentous pseudopodia in enhancing rBMSC osteogenic activity [86], we next evaluated the osteoinductive performance of the scaffolds by measuring alkaline phosphatase (ALP) activity. After 7 days of culture, significant ALP-positive areas were observed in the PB and PBPPt groups (Fig. 8F and S19A). In contrast, the PLLA group showed almost no deep blue positive areas. Quantitative analysis, as indicated in Figure S20A, showed that the PB and PBPPt groups exhibited higher ALP activity, with the highest expression in the PBPPt group. It is widely accepted that mineralized nodule formation indicates osteoblast differentiation and maturation [87]. Therefore, we performed alizarin red S staining to verify the scaffolds’ ability to induce rBMSC mineralization in vitro. The data in Fig. 8G and S19B show significant mineralized nodule formation in the PB and PBPPt groups after 21 days of induction. Quantitative analysis revealed that these groups had significantly more calcium nodules compared to the PLLA group (Figure S20B). The expression of osteogenic differentiation-related genes in rBMSCs was quantified by real-time reverse transcription polymerase chain reaction (qPCR) (Fig. 8H). The results indicated significant upregulation of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osteopontin (OPN), and collagen type I (COL1) in the PB and PBPPt groups after 7 days of co-culture. In conclusion, PLLA bone scaffolds exhibited poor osteogenic activity, whereas the PBPPt scaffolds demonstrated the strongest osteoinductive ability, likely due to the dual action of BG and PDA, which possess strong osteogenic properties.

Fig. 8
figure 8

A) Schematic diagram of in vitro culture of rBMSCs on bone scaffold. B) Cell proliferation as measured by a standard CCK-8 assay at days 1, 4, and 7. C) Viability of rBMSCs cells treated with different conditions. D) Confocal images at different magnifications of rBMSCs after seeding on PLLA, PB and PBPPt scaffolds. E) SEM images of rBMSCs after seeding on PBPPt scaffolds. F) ALP staining of PLLA, PB and PBPPt scaffolds at day 7. G) Alizarin red S staining of PLLA, PB and PBPPt scaffolds at day 21. H) Osteogenic gene expression including COL-1, OCN, OPN, and RUNX-2 of rBMSCs in the PLLA, PB and PBPPt groups on day 7. (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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Assessment of in vivo osteogenic performance

Building on the high biocompatibility and superior osteogenic activity exhibited by the scaffolds in vitro, we further investigated their impact on new bone formation in vivo. To validate the bone repair capability of the PBPPt scaffold in a stress-free environment, a cranial defect model was established in male Sprague-Dawley rats. PLLA, PB, and PBPPt scaffolds were implanted into critical-sized cranial defects [88]. After 12 weeks, cranial defect samples were collected and analyzed using micro-computed tomography (micro-CT) analysis (Fig. 9A). As shown in Fig. 9B, the PLLA group exhibited minimal new bone formation, limited to the edges of the defect, whereas the PB and PBPPt groups displayed extensive new bone generation. Notably, the PBPPt group demonstrated nearly complete filling of the defect area. Quantitative analysis of the region of interest at the defect sites revealed that, consistent with the micro-CT data, the bone volume fraction BV/TV% and bone mineral density (BMD) values of the PB and PBPPt groups were significantly higher than those of the PLLA group, with the PBPPt group showing the best performance (Fig. 9C and D). These results confirm that the PBPPt scaffold significantly accelerates new bone formation and promotes the healing of bone defects.

In addition, 12-week samples were subjected to serial sagittal sectioning and histological analysis. H&E staining (Fig. 9E) revealed that the defect area in the PLLA group was primarily filled with fibrous connective tissue, with only minimal new bone mineral formation. In contrast, the PB and PBPPt groups exhibited extensive new bone formation (NB), with the PBPPt group displaying the most remarkable results, forming a complete bony bridge between the defect area and the host bone. Masson’s trichrome staining (Fig. 9F) further confirmed that the PBPPt group showed significantly higher collagen and osteoid formation within the defect area compared to the PLLA group. The osteoinductive potential of the scaffolds was also assessed through immunofluorescent staining for OCN and OPN. As shown in Figure S21, the PBPPt group exhibited the highest expression levels of OCN and OPN in the defect area, consistent with the in vitro findings. Moreover, H&E staining of major organs (heart, liver, spleen, lungs, and kidneys) from all groups (Figure S22) demonstrated intact cellular structures, indicating good biosafety of the PBPPt composite scaffolds. These results indicate that the PBPPt scaffold significantly accelerates osteogenesis and bone conduction in vivo, showcasing its potential as an ideal implantable scaffold. Overall, in the rat and mouse models used in this study, the PBPPt scaffold exhibited remarkable dual functionality by effectively inhibiting tumor growth and promoting bone defect repair. This provides a novel solution for post-surgical OS treatment while laying a solid foundation for further investigations in large animal models in the future.

Fig. 9
figure 9

A) Schematic diagram of in vivo bone repair using bone scaffold (Created with BioRender.com). B) Three-dimensional reconstructed micro-CT images of bone defect region after implanted for 12 w. Quantification analysis of C) Bone mineral density (BMD), D) Bone tissue volume/total tissue volume (BV/TV). E) Representative images of hematoxylin-eosin (H&E) and F) Masson staining, showing the newly mineralized bone tissue (NB). (ns, no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001)

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Conclusion

In this study, we innovatively developed a Pt (IV) prodrug with low toxicity and on-demand (GSH-responsive) release of chemotherapeutic drugs, which was successfully grafted onto PDA through amidation reactions to synthesize a composite nanomaterial (PDA@Pt). Building on this, PDA@Pt was incorporated into a PB matrix, and a composite bone scaffold with both anti-tumor and bone repair capabilities was successfully constructed using SLS technology. In vitro experiments demonstrated that this bone scaffold possesses suitable mechanical strength, good hydrophilicity, and mineralization capability. Furthermore, based on its excellent photothermal properties and GSH-responsive Pt (II) release behavior, the scaffold effectively inhibited the growth and activity of OS cells in vitro. Additionally, it activated the cGAS-STING signaling pathway by inducing DNA damage, promoting DCs maturation and CD8 + T cell tumor infiltration. In vivo experiments also demonstrated that photothermal-chemotherapy combined with immunotherapy could achieve favorable local anti-osteosarcoma effects. More importantly, due to the integration of BG and PDA, the composite bone scaffold exhibited excellent biocompatibility and bioactivity in vitro and effectively induced osteogenic differentiation of rBMSCs. In in vivo experiments, the bone scaffold gradually biodegraded over 12 weeks, with negligible side effects, while significantly promoting new bone formation. Therefore, this study is the first to introduce a PDA@Pt-based nanoplatform into the field of bone tissue engineering, constructing a biomaterial with both bioactivity and biosafety. This material possesses dual functions of anti-tumor therapy and bone repair, potentially providing an excellent candidate biomaterial system for bone tissue engineering research.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

Funding

This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 82172594、82373046), the Key R & D projects of Department of Science and Technology of Hunan province (No. 2021RC4057), the Hunan Natural Science Fund (No. 2023JJ30855), The Wisdom Accumulation and Talent Cultivation Project of the Third xiangya hosipital of Central South University(YX202001) and the Fundamental Research Funds for the Central Universities of Central South University (No.CX20220313).

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Authors and Affiliations

  1. Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, P. R. China

    Zuyun Yan, Youwen Deng, Liping Huang, Jin Zeng, Dong Wang, Zhaochen Tong, Qizhi Fan, Wei Tan, Xiaofang Zang & Shijie Chen

  2. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410017, P. R. China

    Jinpeng Yan

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  1. Zuyun Yan
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  2. Youwen Deng
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Contributions

Zuyun Yan (Data curation, Formal analysis, Investigation, Methodology, Writing– original draft)Youwen Deng (Conceptualization, Resourcesn)Jin Zeng (Data curation, Validation)Liping Huang (Data curation, Validation)Dong Wang (Formal analysis, Resources)Zhaochen Tong (Formal analysis, Validation)Qizhi Fan (Resources)Wei Tan (Resources)Xiaofang Zang (Formal analysis, Conceptualization, Resources)Jinpeng Yan (Resources, Formal analysis)Shijie Chen (Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Software).

Corresponding author

Correspondence to Shijie Chen.

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Ethics approval and consent to participate

All animal experimental protocols were conducted in accordance with relevant guidelines. The in vivo subcutaneous tumorigenesis experiments were approved by the Ethics Committee of Xiangya Third Hospital, Central South University (BALB/c nude mice, Approval No. XMSB-2023-0164) and the Animal Welfare and Ethics Committee of Central South University (BALB/c mice, Approval No. CSU-2024-0158). The in vivo bone defect repair experiments were approved by the Animal Ethics Committee of Xiangya Third Hospital, Central South University (SD rats, Approval No. XMSB-2022-0007).

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Yan, Z., Deng, Y., Huang, L. et al. Biopolymer-based bone scaffold for controlled Pt (IV) prodrug release and synergistic photothermal-chemotherapy and immunotherapy in osteosarcoma. J Nanobiotechnol 23, 286 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12951-025-03253-w

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Journal of Nanobiotechnology

ISSN: 1477-3155

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