Mitochondria-Targeted Nanoadjuvants Induced Multi-Functional Immune-Microenvironment Remodeling to Sensitize Tumor Radio-Immunotherapy.

It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand-1 (PD-L1) overexpression and transforming growth factor-ß (TGF-ß) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi-immune pathway regulation strategy through PD-L1, collagen, and TGF-ß co-depression. Then, IR-LND is prepared by combining the mitochondria-targeted molecule IR-68 with LND, which then is loaded with liposomes (Lip) to create IR-LND@Lip nanoadjuvants. By doing this, IR-LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD-L1, collagen, and TGF-ß co-inhibition. In conclusion, the combined treatment of RT and IR-LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.

Epigenetic-related gene-based prognostic model construction and validation in prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD), driven by both genetic and epigenetic factors, is a common malignancy that affects men worldwide. We aimed to identify and characterize differentially expressed epigenetic-related genes (ERGs) in PRAD and investigate their potential roles in disease progression and prognosis. We used PRAD samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify prognosis-associated ERGs. Thirteen ERGs with two distinct expression profiles were identified through consensus clustering. Gene set variation analysis highlighted differences in pathway activities, particularly in the Hedgehog and Notch pathways. Higher epigenetic scores correlated with favorable prognosis and improved immunotherapeutic response. Experimental validation underscored the importance of CBX3 and KAT2A, suggesting their pivotal roles in PRAD. This study provides crucial insights into the epigenetic scoring approach and presents a promising prognostic tool, with CBX3 and KAT2A as key players. These findings pave the way for targeted and personalized interventions for the treatment of PRAD.

Inorganic Pyrophosphate at Serum Concentration May Not Be Able to Inhibit Mineralization: A Study in Aqueous Solutions and Serum.

The constituent ions of calcium phosphate in body fluids are in the supersaturated state and tend to form minerals physiologically or pathologically. Inorganic pyrophosphate (PPi) has been considered as one of the most important inhibitors against the formation of calcium phosphate minerals. However, serum PPi concentrations in humans are maintained at a level of several µmol/L, and its effectiveness and mechanism for mineralization inhibition remain ambiguous. Therefore, this work studied the mineralization process in an aqueous solution, explored the effective inhibitory concentration of PPi by titration, and characterized the species during the reactions. We find that PPi at a normal serum concentration does not inhibit mineralization significantly. Such a conclusion was further confirmed in the PPi-added serum. This work indicates that PPi may not be a major direct inhibitor of mineralization in serum and possibly functions via alternative mechanisms.

A novel trauma induced urethral stricture in rat model.

Urethral stricture (US) is a longstanding disease, while there has not existed a suitable animal model to mimic the condition. We aimed to establish a trauma-induced US animal model to simulate this clinical scenario. A total of 30 rats were equally distributed into two groups, sham and US group. All rats were anesthetized with isoflurane and undergone cystostomy. In the US group, a 2 mm incision was made in the urethra and sutured to induce US. The sham group only make a skin incision on the ventral side of the anterior urethra. 4 weeks later, ultrasound and cystourethrography were performed to evaluate the degree of urethral stricture, pathological examinations were carried out to evaluate the degree of fibrosis. Urodynamic evaluation and mechanical tissue testing were performed to evaluate the bladder function and urethral tissue stiffness. The results showed that the urethral mucosa was disrupted and urethral lumen was stenosed in the US group. Additionally, the US group showed elevated bladder pressure, prolonged micturition intervals and increased tissue stiffness. In conclusion, the rat urethral stricture model induced by trauma provides a closer representation of the real clinical scenario. This model will significantly contribute to advancing research on the mechanisms underlying traumatic urethral stricture.

Quercetin-3-O-glc-1-3-rham-1-6-glucoside decreases Aß production, inhibits Aß aggregation and neurotoxicity, and prohibits the production of inflammatory cytokines.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aß) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aß oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aß is derived from the sequential cleavage of amyloid-ß precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aß generation and anti-Aß aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aß production by reducing ß-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aß oligomer formation by directly binding to Aß. Moreover, YCC31 could attenuate Aß-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD.

Rehabilitation exercise-driven symbiotic electrical stimulation system accelerating bone regeneration.

Electrical stimulation can effectively accelerate bone healing. However, the substantial size and weight of electrical stimulation devices result in reduced patient benefits and compliance. It remains a challenge to establish a flexible and lightweight implantable microelectronic stimulator for bone regeneration. Here, we use self-powered technology to develop an electric pulse stimulator without circuits and batteries, which removes the problems of weight, volume, and necessary rigid packaging. The fully implantable bone defect electrical stimulation (BD-ES) system combines a hybrid tribo/piezoelectric nanogenerator to provide biphasic electric pulses in response to rehabilitation exercise with a conductive bioactive hydrogel. BD-ES can enhance multiple osteogenesis-related biological processes, including calcium ion import and osteogenic differentiation. In a rat model of critical-sized femoral defects, the bone defect was reversed by electrical stimulation therapy with BD-ES and subsequent bone mineralization, and the femur completely healed within 6 weeks. This work is expected to advance the development of symbiotic electrical stimulation therapy devices without batteries and circuits.

The human microbiome and benign prostatic hyperplasia: Current understandings and clinical implications.

The research of the human microbiome in the preceding decade has yielded novel perspectives on human health and diseases. Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly males, which negatively affects the life quality. Existing evidence has indicated that the human microbiome, including urinary, intra-prostate, gut, oral and blood microbiome may exert a significant impact on the natural progression of BPH. The dysbiosis of the microbiome may induce inflammation at either a local or systemic level, thereby affecting the BPH. Moreover, metabolic syndrome (MetS) caused by the microbiome can also be involved in the development of BPH. Additionally, alterations in the microbiome composition during the senility process may serve as another cause of the BPH. Here, we summarize the influence of human microbiome on BPH and explore how the microbiome is linked to BPH through inflammation, MetS, and senility. In addition, we propose promising areas of investigation and discuss the implications for advancing therapeutic approaches.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.

Amorphous 1-D nanowires of calcium phosphate/pyrophosphate: A demonstration of oriented self-growth of amorphous minerals.

Amorphous inorganic solids are traditionally isotropic, thus, it is believed that they only grow in a non-preferential way without the assistance of regulators, leading to the morphologies of nanospheres or irregular aggregates of nanoparticles. However, in the presence of (ortho)phosphate (Pi) and pyrophosphate ions (PPi) which have synergistic roles in biomineralization, the highly elongated amorphous nanowires (denoted ACPPNs) form in a regulator-free aqueous solution (without templates, additives, organics, etc). Based on thorough characterization and tracking of the formation process (e.g., Cryo-TEM, spherical aberration correction high resolution TEM, solid state NMR, high energy resolution monochromated STEM-EELS), the microstructure and its preferential growth behavior are elucidated. In ACPPNs, amorphous calcium orthophosphate and amorphous calcium pyrophosphate are distributed at separated but close sites. The ACPPNs grow via either the preferential attachment of ∼2 nm nanoclusters in a 1-dimension way, or the transformation of bigger nanoparticles, indicating an inherent driving force-governed process. We propose that the anisotropy of ACPPNs microstructure, which is corroborated experimentally, causes their oriented growth. This study proves that, unlike the conventional view, amorphous minerals can form via oriented growth without external regulation, demonstrating a novel insight into the structures and growth behaviors of amorphous minerals.

Performance Test of a Well-Trained Model for Meningioma Segmentation in Health Care Centers: Secondary Analysis Based on Four Retrospective Multicenter Data Sets.

BACKGROUND: Convolutional neural networks (CNNs) have produced state-of-the-art results in meningioma segmentation on magnetic resonance imaging (MRI). However, images obtained from different institutions, protocols, or scanners may show significant domain shift, leading to performance degradation and challenging model deployment in real clinical scenarios. OBJECTIVE: This research aims to investigate the realistic performance of a well-trained meningioma segmentation model when deployed across different health care centers and verify the methods to enhance its generalization. METHODS: This study was performed in four centers. A total of 606 patients with 606 MRIs were enrolled between January 2015 and December 2021. Manual segmentations, determined through consensus readings by neuroradiologists, were used as the ground truth mask. The model was previously trained using a standard supervised CNN called Deeplab V3+ and was deployed and tested separately in four health care centers. To determine the appropriate approach to mitigating the observed performance degradation, two methods were used: unsupervised domain adaptation and supervised retraining. RESULTS: The trained model showed a state-of-the-art performance in tumor segmentation in two health care institutions, with a Dice ratio of 0.887 (SD 0.108, 95% CI 0.903-0.925) in center A and a Dice ratio of 0.874 (SD 0.800, 95% CI 0.854-0.894) in center B. Whereas in the other health care institutions, the performance declined, with Dice ratios of 0.631 (SD 0.157, 95% CI 0.556-0.707) in center C and 0.649 (SD 0.187, 95% CI 0.566-0.732) in center D, as they obtained the MRI using different scanning protocols. The unsupervised domain adaptation showed a significant improvement in performance scores, with Dice ratios of 0.842 (SD 0.073, 95% CI 0.820-0.864) in center C and 0.855 (SD 0.097, 95% CI 0.826-0.886) in center D. Nonetheless, it did not overperform the supervised retraining, which achieved Dice ratios of 0.899 (SD 0.026, 95% CI 0.889-0.906) in center C and 0.886 (SD 0.046, 95% CI 0.870-0.903) in center D. CONCLUSIONS: Deploying the trained CNN model in different health care institutions may show significant performance degradation due to the domain shift of MRIs. Under this circumstance, the use of unsupervised domain adaptation or supervised retraining should be considered, taking into account the balance between clinical requirements, model performance, and the size of the available data.

Extracellular matrix stiffness aggravates urethral stricture through Igfbp3/Smad pathway.

Urethral stricture refers to the narrowing of the urethral lumen. While previous studies have hinted at inflammation as the initial driver of this condition, the reasons and mechanisms behind its progression remain largely unknown. By Atomic force microscope (AFM), researchers measured the matrix stiffness of urethra to be 5.23 ± 0.37 kPa for normal tissue and 41.59 ± 2.48 kPa for stricture urethral scar. Similar results were observed in rat urethral stricture models, where the matrix stiffness of normal urethra was 4.29 ± 0.82 kPa, while 32.94 ± 7.12 kPa for urethral stricture scar. Notably, the matrix stiffness increased in rat models over time. To further investigate, polyacrylamide hydrogels were employed to mimic different levels of stiffness for normal and stricture condition. Interestingly, higher matrix stiffness led to an increased fibroblast-to-myofibroblast transition (FMT) in rat urethral fibroblasts, indicated by enhanced expression of α-SMA and Collagen I, as well as changing in the morphology of fibroblast. RNA-seq analysis suggested that Igfbp3/Smads might regulate the progressive FMT in urethral stricture. In the experiment where the expression of Igfbp3 was inhibited, increasing matrix stiffness lose the potential to stimulate FMT progression and the expression of p-Smad2/3 decreased. On the contrary, overexpression of Igfbp3 promoted the process of FMT in urethral fibroblasts. In conclusion, Igfbp3/Smad pathway appeared to be involved in the progression of urethral fibrosis. This finding suggested that Igfbp3/Smad might be an promising target for future research and treatment in this filed.

Combination of hsa_circ_0004674 and lncRNA OIP5­AS1 as a novel clinical biomarker used to predict prognosis in patients with osteosarcoma.

Osteosarcoma is a malignant tumor that predominantly occurs in children or adolescents under the age of 20 years old. Metastasis and chemotherapy resistance are two problems in the treatment of osteosarcoma, and the lack of definite biomarkers impairs the course of treatment. In recent years, non-coding RNA, as a biomarker of osteosarcoma, has become an area of research focus. The role of long non-coding RNAs (lncRNAs), such as lncRNA OIP5-AS1, and circular RNAs, such as hsa_circ_0004674, in osteosarcoma have previously been revealed, and the present study investigated their clinical significance. A total of 20 samples were collected from patients with osteosarcoma. The expression levels of lncRNA OIP5-AS1 and hsa_circ_0004674 were analyzed in tumor tissues and patient serum, and their associations with chemotherapy sensitivity, lung metastasis and prognosis were assessed. The results revealed that these two non-coding RNAs were significantly upregulated in the osteosarcoma tissues of patients compared with those in the adjacent tumor tissues. In addition, the expression levels of the two non-coding RNAs were increased in the serum of patients with osteosarcoma compared with those in patients with bone fractures (P<0.01). In patients with lung metastasis or chemotherapy resistance (tumor necrosis rate <90%), the expression levels of the two non-coding RNAs were similarly increased. By plotting the receiver operating characteristic curve, it was revealed that the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 was better than ALP or either non-coding RNA alone in predicting chemotherapy sensitivity and metastasis. Kaplan-Meier survival analysis showed that, in patients with osteosarcoma, higher expression of both non-coding RNAs was associated with worse survival time (log-rank test P=0.006). In conclusion, the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 may be used as a better biomarker than traditional biomarkers, such as ALP, in a clinical setting.

Mineralized Enzyme-Based Biomaterials with Superior Bioactivities for Bone Regeneration.

The formation and metabolic balance of bone tissue is a controllable process of biomineralization, which is regulated by various cells, biomolecules, and ions. Enzyme molecules play an important role in this process, and alkaline phosphatase (ALP) is one of the most critical factors. In this study, inspired by the process of bone biomineralization, a biomimetic strategy is achieved for the preparation of mineralized ALP nanoparticles (MALPNs), by taking advantages of the unique reaction between ALP and calcium ions in Dulbecco's modified Eagle's medium. Benefiting from the mild biomineralization reaction, the MALPN system highly maintains the activity of ALP. Furthermore, the in vitro studies show that the MALPN system significantly enhances the proliferation of bone marrow mesenchymal stem cells and upregulates their osteogenic differentiation. When evaluated as synthetic graft materials for bone regeneration, the MALPN-incorporated gelatin methacryloyl graft shows excellent mechanical properties, a sustained release profile of ALP, and high biocompatibility and efficacy in guiding bone regeneration and vascularization for critical-sized rat calvarial defect. Moreover, we also demonstrate that the biomimetic mineralization strategy can be adopted for other proteins such as acid phosphatase, bovine serum albumin, fibrinogen, and gelatin, suggesting its universality for constructing mineralized protein-/enzyme-based bioactive materials for the application of tissue regeneration.

Multi-walled Carbon Nanotubes Remediate the Phytotoxicity of Quinclorac to Tomato.

In order to remediate the phytotoxicity of quinclorac to tomato by multi-walled carbon nanotubes (MWCNTs), the adsorption of quinclorac to MWCNTs was monitored and the effect of MWCNTs on the phytotoxicity of quinclorac to tomato in soil were studied. The results showed that the Linear equation and Freundlich equation can well fit the adsorption isotherm of quinclorac in the soil containing MWCNTs. The adsorption of quinclorac in soil was significantly enhanced by the addition of MWCNTs; the Kd of soil (1% MWCNTs) was 28.7 times of pure soil. The quinclorac had an obvious inhibitory effect on the growth of tomatoes; serious phytotoxicity was also induced even at the lowest concentration of 0.025 mg/kg. With the MWCNTs content in soil increased to 0.5% and 1%, the phytotoxicity of quinclorac to tomatoes decreased significantly, and the height and fresh weight of tomatoes were even higher than those of the control group, indicating that MWCNTs can promote the growth of tomato. These results provide a reference for resolving the problem of phytotoxicity induced by residual herbicides in farmland.

Transperitoneal Laparoscopic Unroofing versus Fenestration Under Seminal Vesiculoscopy for Seminal Vesicle Cyst, a Multi-Institutional Retrospective Cohort Study.

Background: To illustrate the transperitoneal laparoscopic unroofing (TLU) and compare the efficacy and safety of TLU to fenestration under seminal vesiculoscopy (FUSV) in treating symptomatic seminal vesicle cyst (SVC). Methods: We retrospectively reviewed all patients with symptomatic SVC who underwent TLU or FUSV between 2008 and 2020 at 3 institutions in Hunan. The two groups were evaluated with reference to radiological failure-free survival (R-FFS), fertility outcome, symptoms, and complications at a median 33.5-month follow-up. Results: Of the 98 males, 58 (59.2%) received TLU, and 40 (40.8%) underwent FUSV. Baseline characteristics were comparable. Semen analysis, prostatitis-like symptoms, and the maximum diameter of cyst were partially improved after both surgeries at 12-month follow-up. The TLU groups suggested a higher incidence rate of fertility for SVC patients with comorbid infertility compared with the FUSV group (82.4% vs 70.3%, p = 0.041), as well as better R-FFS of cysts at five-year follow-up (Log rank test, p = 0.021). In addition, the number of patients with NIH-CPSI (National Institutes of Health Chronic Prostatitis Symptom Index) scores higher than 15 decreased more significantly after TLU (p = 0.004). Except for hematospermia within 3 months, no significant difference in adverse events was observed in the two groups during the long-term follow-up. Conclusion: TLU was superior for patients with large and symptomatic SVC to FUSV, with more relieved symptoms, better R-FFS of cysts and fertility outcomes. Registration Number of Clinical Trial: ChiCTR2100053850 in Chinese Clinical Trial Registry Platform (ChiCTR).

Platelet-Activating Biominerals Enhanced Injectable Hydrogels With Superior Bioactivity for Bone Regeneration.

Refractory bone fracture, which is difficult to be treated, is a common clinical disease. Taking inspiration from the natural process of bone regeneration, we provide a biomimetic strategy to develop a new injectable biomaterial for repairing bone defects, which is mainly composed of platelets, fibrins, and biominerals. Biomineral nanoparticles (EACPNs) with an amorphous phase are prepared by an enzyme-catalyzed route and display a platelet-activating property. The composite hydrogel (EPH) of EACPNs, fibrins, and platelets is injectable, and has similar chemical properties to natural materials in bone regeneration. The dried EPH samples display a highly porous structure, which would be favorable for cell attachment and growth. The results from in vitro studies indicate that EPH has high biocompatibility and superior bioactivity in promoting the osteogenic differentiation of rat bone marrow stem cells (rBMSCs). Furthermore, the results from in vivo studies clearly indicate that EPH can induce the formation of new collagen and vessels in the defect area, thus leading to faster regeneration of bone defects at 2 weeks. Our study provides a strategy for designing new biomimetic materials, which may be favorable in the treatment of refractory bone fracture.

Photothermal-triggered immunogenic nanotherapeutics for optimizing osteosarcoma therapy by synergizing innate and adaptive immunity.

Inadequate immune response remains a critical cause of immunotherapy failure in various tumor treatments. Herein, we offer a new approach to achieve a cross-talk between innate and adaptive immune responses based on a new nanoplatform for photothermal therapeutics. The nanoplatform was formed by linking titanium carbide MXene with Mn2+-contained ovalbumin (OVA), where it can trigger efficient mt-DNA presentation and the release of OVA and Mn2+ upon the irradiation of near-infrared laser. More importantly, the released mt-DNA and Mn2+ synergistically activate innate immunity via the cGAS-stimulator of the interferon genes signaling pathway, and the OVA and protein antigens from tumor cells enhance adaptive immunity. Furthermore, in an osteosarcoma model, we observed that the proposed nanoplatform leads to the effective presentation of tumor antigens, which boost the maturation of dendritic cells (DCs) to the hilt and thus improve the infiltration of cytotoxic T lymphocyte in primary and distant tumors. Collectively, our work not only demonstrates a method for constructing a new nanoplatform for photothermal therapeutics but also provides a general strategy for synchronously activating innate and adaptive immunities to promote the maturation of DCs for antimetastasis tumor therapy.

Biomineralization-inspired synthesis of amorphous manganese phosphates for GLUT5-targeted drug-free catalytic therapy of osteosarcoma.

Osteosarcoma, occurring most frequently in children, teens, and young adults, is a lethal bone cancer with a high incidence of distant metastases and drug resistance. Developing a therapeutic platform that integrates targeting, curing and imaging is highly desirable for enhanced osteosarcoma therapy, yet quite challenging. In this work, we demonstrate a novel biomineralization-inspired strategy for the synthesis of a fructose incorporated manganese phosphate (Fru-MnP) nanoplatform for tumour targeting, drug-free therapy, and MRI imaging. Benefitting from the glucose transporter 5 (GLUT5)-mediated endocytosis, our Fru-MnP nanoplatform produces a high level of reactive oxygen species (ROS) via the Mn2+-driven Fenton reaction within osteosarcoma cells, leading to efficient cancer cell killing due to caspase-mediated apoptosis. By virtue of the T1 signal enhancement of Mn2+, our Fru-MnP nanoplatform also acts as an effective tumour-specific MRI contrast agent, realizing the MRI-monitored chemodynamic therapy. The proposed synergistic therapeutic platform opens new possibilities for high efficacy therapy for osteosarcoma.