Determination of aloesone in rat plasma by LC-MS/MS spectrometry and its application in a pharmacokinetic study.

Aim: We aimed to develop a rapid and accurate LC-MS/MS method for determining the concentration of aloesone in rat plasma, and to investigate its pharmacokinetics. Methods: The rat plasma samples were extracted using acetonitrile. Chromatographic separation was achieved using a Kinetex XB-C18 column, with a mobile phase of methanol and water (containing 0.1‰ formic acid) in a gradient elution. An ESI source, operating in positive ion mode with multiple reaction monitoring, was utilized. Results & conclusion: The developed method meets all the requirements for methodological validation, and it was successfully applied in the pharmacokinetic study. It was observed that oral administration of aloesone in rats resulted in rapid absorption (time to reach Cmax: 0.083 h) but low bioavailability (12.59%).

A review of typical biological activities of glycyrrhetinic acid and its derivatives.

Glycyrrhetinic acid, a triterpenoid compound primarily sourced from licorice root, exhibits noteworthy biological attributes, including anti-inflammatory, anti-tumor, antibacterial, antiviral, and antioxidant effects. Despite these commendable effects, its further advancement and application, especially in clinical use, have been hindered by its limited druggability, including challenges such as low solubility and bioavailability. To enhance its biological activity and pharmaceutical efficacy, numerous research studies focus on the structural modification, associated biological activity data, and underlying mechanisms of glycyrrhetinic acid and its derivatives. This review endeavors to systematically compile and organize glycyrrhetinic acid derivatives that have demonstrated outstanding biological activities over the preceding decade, delineating their molecular structures, biological effects, underlying mechanisms, and future prospects for assisting researchers in finding and designing novel glycyrrhetinic acid derivatives, foster the exploration of structure-activity relationships, and aid in the screening of potential candidate compounds.

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases.

An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 µM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

Stimuli-responsive electrospun nanofibers for drug delivery, cancer therapy, wound dressing, and tissue engineering.

The stimuli-responsive nanofibers prepared by electrospinning have become an ideal stimuli-responsive material due to their large specific surface area and porosity, which can respond extremely quickly to external environmental incitement. As an intelligent drug delivery platform, stimuli-responsive nanofibers can efficiently load drugs and then be stimulated by specific conditions (light, temperature, magnetic field, ultrasound, pH or ROS, etc.) to achieve slow, on-demand or targeted release, showing great potential in areas such as drug delivery, tumor therapy, wound dressing, and tissue engineering. Therefore, this paper reviews the recent trends of stimuli-responsive electrospun nanofibers as intelligent drug delivery platforms in the field of biomedicine.

A Potential Anti-Glioblastoma Compound LH20 Induces Apoptosis and Arrest of Human Glioblastoma Cells via CDK4/6 Inhibition.

Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM.

Fibulin-2: A potential regulator of immune dysfunction after bone trauma.

OBJECTIVES: To reveal the relationship between the fibulin-2 protein and immune dysfunction after bone trauma. METHODS: Individuals who were admitted to the study were divided into a bone trauma group, a recovered from bone trauma group and a volunteer without bone trauma group based on the reason for admission. Fibulin-2 levels in the three groups were compared. Fibulin-2-knockout (fibulin-2-/- ) mice and wild-type (WT) mice were used to detect susceptibility to infection. Hematoxylin and eosin (HE) staining and immunohistochemical staining were employed to observe pathological changes in each organ from fibulin-2-/- mice and WT mice. RESULTS: In total, 132 patients were enrolled in this study. The fibulin-2 level in the bone trauma group was lower than that in the recovered bone trauma group (3.39 ± 1.41 vs. 4.30 ± 1.38 ng/mL, t = 2.948, p < .05) and also lower than that in the volunteers without bone trauma group (3.39 ± 1.41 vs. 4.73 ± 1.67 ng/mL, t = 4.135, p < .05). Fibulin-2-/- mice are more prone to infection. Compared with those in WT mice, spleen function and thymus function in fibulin-2-/- mice were impaired. Immunohistochemical staining revealed that compared with those in WT mice, significantly fewer CD4+ T cells, CD8+ T cells, and CD19+ B cells were noted in the spleen and thymus of fibulin-2-/- mice. CONCLUSIONS: The plasma fibulin-2 level was lower in patients with bone trauma. Decreased fibulin-2 is associated with immune dysfunction after bone trauma.

Multiple Beneficial Effects of Aloesone from Aloe vera on LPS-Induced RAW264.7 Cells, Including the Inhibition of Oxidative Stress, Inflammation, M1 Polarization, and Apoptosis.

Aloesone is a major metabolic compound in Aloe vera, which has been widely used as a food source and therapeutic agent in several countries. Our recent study demonstrated that aloesone has anti-epileptic effects on glutamate-induced neuronal injury by suppressing the production of reactive oxygen species (ROS). Unless ROS are naturally neutralized by the endogenous antioxidant system, they lead to the activation of inflammation, polarization, and apoptosis. This study aimed to identify the multiple beneficial effects of aloesone and explore its molecular mechanism in macrophages. Hence, the murine macrophage cell line RAW264.7 was pretreated with aloesone and then exposed to lipopolysaccharides (LPS). The results demonstrated that aloesone, within a dosage range of 0.1-100 µM, dramatically decreased the LPS-induced elevation of ROS production, reduced nitric oxide (NO) release, inhibited the M1 polarization of RAW264.7 cells, and prevented cells from entering the LPS-induced early and late phases of apoptosis in a dose-dependent manner. Simultaneously, aloesone significantly decreased the mRNA expression of inflammation-related genes (iNOS, IL-1ꞵ, TNF-α) and increased the expression of antioxidant enzymes (Gpx-1 and SOD-1). The core genes HSP90AA1, Stat3, Mapk1, mTOR, Fyn, Ptk2b, and Lck were closely related to these beneficial effects of aloesone. Furthermore, immunofluorescence staining and flow cytometry data confirmed that aloesone significantly repressed the activation of mTOR, p-mTOR, and HIF-1α induced by LPS and inhibited the protein expression of TLR4, which is the target of LPS. In conclusion, aloesone demonstrated multiple protective effects against LPS-induced oxidative stress, inflammation, M1 polarization, and apoptosis in macrophages, suggesting its potential as a prodrug.

Fibulin2: a negative regulator of BMSC osteogenic differentiation in infected bone fracture healing.

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone.

Silk Fibroin Combined with Electrospinning as a Promising Strategy for Tissue Regeneration.

The development of tissue engineering scaffolds is of great significance for the repair and regeneration of damaged tissues and organs. Silk fibroin (SF) is a natural protein polymer with good biocompatibility, biodegradability, excellent physical and mechanical properties and processability, making it an ideal universal tissue engineering scaffold material. Nanofibers prepared by electrospinning have attracted extensive attention in the field of tissue engineering due to their excellent mechanical properties, high specific surface area, and similar morphology as to extracellular matrix (ECM). The combination of silk fibroin and electrospinning is a promising strategy for the preparation of tissue engineering scaffolds. In this review, the research progress of electrospun silk fibroin nanofibers in the regeneration of skin, vascular, bone, neural, tendons, cardiac, periodontal, ocular and other tissues is discussed in detail.

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy.

AIMS: Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance. METHODS: Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score14th-before ≤0) and latent time (latent time14th-before ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy. Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed. RESULTS: Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5. CONCLUSION: Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.

Up-and-coming anti-epileptic effect of aloesone in Aloe vera: Evidenced by integrating network pharmacological analysis, in vitro, and in vivo models.

Background: Aloe vera is a medically valuable plant with anti-epileptic activity; however, its mechanism of action remains unknown. In this study, network pharmacological, in vitro, and in vivo experiments were carried out to explore the potential anti-epileptic components and targets of Aloe vera. Methods: The main active components of Aloe vera were identified by searching the Traditional Chinese Medicine System Pharmacology database. Targets of Aloe vera were predicted using SwissTargetPrediction, whereas information about the epilepsy disease targets was obtained from Gene Cards. The protein-protein interaction network and core targets were screened according to the topological structure and CytoNCA plugin. The glutamate-induced HT22 cell line and pentylenetetrazol-induced seizure rats were used to confirm the effect of aloesone by detecting reactive oxygen species (ROS) and apoptosis, and predicting the targets. Results: A total of 14 core active components were selected based on the screening criteria of oral bioavailability ≥30% and drug-likeness ≥ 0.10. Four compounds, namely linoleic acid, aloesone, isoeleutherol glucosiden qt, and anthranol, demonstrated the potential ability of crossing the blood-brain barrier. A total of 153 targets associated with epilepsy were predicted for the four compounds. Moreover, after network analysis with CytoNCA, 10 targets, namely, MAPK1, SRC, MARK3, EGFR, ESR1, PTGS2, PTPN11, JAK2, PPKCA, and FYN, were selected as the core genes, and SRC, which has been predicted to be the target of aloesone and anthranol, exhibited the highest subgraph centrality value. In vitro experiments confirmed that aloesone treatment significantly inhibited the glutamate-induced neuronal injury by reducing the intracellular ROS content and the early phase of apoptosis. Additionally, treatment with 50 mg/kg aloesone resulted in anti-seizure effects by reducing the seizure score and prolonging the latent period in acute and chronic rats. Furthermore, aloesone treatment increased the phosphorylation of c-SRC at Y418 and reduced the phosphorylation at Y529, simultaneously activating c-SRC. Conclusion: Integrating network pharmacology with in vitro and in vivo experiments demonstrated that aloesone, which inhibited seizure by activating c-SRC, is a potential anti-seizure compound present in Aloe vera.

Application of BMP in Bone Tissue Engineering.

At present, bone nonunion and delayed union are still difficult problems in orthopaedics. Since the discovery of bone morphogenetic protein (BMP), it has been widely used in various studies due to its powerful role in promoting osteogenesis and chondrogenesis. Current results show that BMPs can promote healing of bone defects and reduce the occurrence of complications. However, the mechanism of BMP in vivo still needs to be explored, and application of BMP alone to a bone defect site cannot achieve good therapeutic effects. It is particularly important to modify implants to carry BMP to achieve slow and sustained release effects by taking advantage of the nature of the implant. This review aims to explain the mechanism of BMP action in vivo, its biological function, and how BMP can be applied to orthopaedic implants to effectively stimulate bone healing in the long term. Notably, implantation of a system that allows sustained release of BMP can provide an effective method to treat bone nonunion and delayed bone healing in the clinic.

Intelligent Nanotransducer for Deep-Tumor Hypoxia Modulation and Enhanced Dual-Photosensitizer Photodynamic Therapy.

Upconversion nanoparticles (UCNPs) emerged as promising near-infrared (NIR) light-triggered nanotransducers for photodynamic therapy (PDT). However, the traditionally used 980 nm excitation source could cause an overheating effect on biological tissues, and the single photosensitizer (PS) loading could not efficiently utilize multiradiation UC luminescence, resulting in a limited efficiency of PDT in tumor tissues with hypoxia characteristics. Herein, 808 nm light-responsive Nd-sensitized UCNPs@mSiO2@MnO2 core-shell NPs were designed as light nanotransducers with efficient UC emission at 550 and 650 nm for PDT and downshifting luminescence at 1525 nm for second NIR (NIR-II) imaging. UC emission was fully utilized by loading dual PSs, rose bengal (RB), and zinc phthalocyanine (ZnPc), thus significantly improving the reactive oxide species (ROS) generation efficiency. Moreover, a manganese dioxide (MnO2) shell with ultrasensitive biodegradability in an acidic tumor microenvironment (TME) can generate an amount of oxygen molecules, alleviating the symptoms of hypoxia and then improving the efficacy of PDT. Meanwhile, the biodegraded Mn2+ ions can further strengthen T1-weighted magnetic resonance imaging (MRI). This work presented a new multifunctional theranostic agent for combining NIR-II/MRI imaging and 808 nm light-triggered PDT to combat the limitations of cancer therapy.

In Vivo High-Resolution Bioimaging of Bone Marrow and Fracture Diagnosis Using Lanthanide Nanoprobes with 1525 nm Emission.

Bones play vital roles in human health. Noninvasive visualization of the full extent of bones is highly demanded to evaluate many bone-related diseases. Herein, we report poly (acrylic acid) (PAA)-modified NaLuF4:Yb/Er/Gd/Ce@NaYF4 nanoparticles (PAA-Er) with second near-infrared emission beyond 1500 nm (also referred as NIR-IIb) for high-resolution bone/bone marrow imaging and bone fracture diagnosis. The NIR-IIb optical-guided bone marrow imaging presents a high signal to noise ratio, which is superior to that for imaging in the NIR-II window (1000-1400 nm, NIR-IIa). Importantly, we also investigated the size-dependent accumulation of the nanoparticles and the possible accumulation mechanism of the designed PAA-Er nanoprobes in bone marrow. Due to the high affinity capability of the PAA-Er nanoprobes, a highly sensitive NIR-IIb optical-guided bone fracture diagnosis was successfully achieved. This novel technology paves the way to design lanthanide nanoprobes for NIR-IIb optical-guided high-resolution bone marrow imaging and bone-related disease diagnosis.

A Clinical Diagnostic Study: Fibulin-2 is a Novel Promising Biomarker for Predicting Infection.

INTRODUCTION: Infection remains a major cause of morbidity and mortality in hospital. As uncontrolled early infection may develop into systemic infection and eventually progress to sepsis, it is important to address infection at an early stage. Furthermore, early detection and prompt diagnosis of infection are the basis of clinical intervention. However, as a result of the interference of complex aetiologies, including fever and trauma, problems regarding the sensitivity and specificity of current diagnostic indices remain, such as for C-reactive protein (CRP), procalcitonin (PCT), white blood cells (WBC), neutrophil ratio (NEU%), interleukin-6 (IL-6) and D-dimer. As a result, there is an urgent need to develop new biomarkers to diagnose infection. METHODS: From January to October 2021, consecutive patients in the emergency department (ED) were recruited to investigate the feasibility of fibulin-2 as a diagnostic indicator of early infection. Fibulin-2 concentrations in plasma were determined with enzyme-linked immunosorbent assay (ELISA). The performance of fibulin-2 for predicting infection was analysed by receiver operating characteristic (ROC) curves. RESULTS: We found that the plasma fibulin-2 level was elevated in patients with infection compared with those without infection. ROC curve analysis showed that the area under the curve (AUC) for fibulin-2 was 0.712. For all patients included, the diagnostic ability of fibulin-2 (AUC 0.712) performed as well as CRP (AUC 0.667) and PCT (AUC 0.632), and better than WBC (AUC 0.620), NEU% (AUC 0.619), IL-6 (AUC 0.561) and D-dimer (AUC 0.630). In patients with fever, fibulin-2 performed as well as PCT and better than the other biomarkers in infection diagnosis. In particular, fibulin-2 performed better than all these biomarkers in patients with trauma. CONCLUSION: Fibulin-2 is a novel promising diagnostic biomarker for predicting infection.

One-Pot Synthesis of α-Ketoamides from α-Keto Acids and Amines Using Ynamides as Coupling Reagents.

A one-pot strategy for α-keto amide bond formation have been developed by using ynamides as coupling reagents under extremely mild reaction conditions. Diversely structural α-ketoamides were afforded in up to 98% yield for 36 examples. This reaction features advantages such as practical coupling procedure, wide functional group tolerance, and extremely mild conditions and has potential applications in synthetic and medicinal chemistry.

Clindamycin-loaded titanium prevents implant-related infection through blocking biofilm formation.

Implant-related infection is a disastrous complication. Surface modification of titanium is considered as an important strategy to prevent implant-related infection. However, there is no recognized surface modification strategy that can be applied in clinic so far. We explored a new strategy of coating. The clindamycin-loaded titanium was constructed by layer-by-layer self-assembly. The release of clindamycin from titanium was detected through high performance liquid chromatography. Different titanium was co-cultured with Staphylococcus aureus for 24 h in vitro, then the effect of different titanium on bacterial colonization and biofilm formation was determined by spread plate method and scanning electron microscopy. Cytotoxicity and cytocompatibility of clindamycin-loaded titanium on MC3T3-E1 cells were measured by CCK8. The antibacterial ability of clindamycin-loaded titanium in vivo was also evaluated using a rat model of osteomyelitis. The number of osteoclasts in bone defect was observed by tartrate-resistant acid phosphatase staining. Bacterial burden of surrounding tissues around the site of infection was calculated by tissue homogenate and colony count. Clindamycin-loaded titanium could release clindamycin slowly within 160 h. It reduced bacterial colonization by three orders of magnitude compare to control (p < .05) and inhibits biofilm formation in vitro. Cells proliferation and adhesion were similar on three titanium surfaces (p > .05). In vivo, clindamycin-loaded titanium improved bone healing, reduced microbial burden, and decreased the number of osteoclasts compared control titanium in the rat model of osteomyelitis. This study demonstrated that clindamycin-loaded titanium exhibited good biocompatibility, and showed antibacterial activity both in vivo and in vitro. It is promising and might have potential for clinical application.

Sustained Release of VEGF to Promote Angiogenesis and Osteointegration of Three-Dimensional Printed Biomimetic Titanium Alloy Implants.

Tumor resection and treatment of trauma-related regional large bone defects have major challenges in the field of orthopedics. Scaffolds that treat bone defects are the focus of bone tissue engineering. 3D printing porous titanium alloy scaffolds, prepared via electron beam melting technology, possess customized structure and strength. The addition of a growth factor coating to the scaffold introduces a specific form of biological activation. Vascular endothelial growth factor (VEGF) is key to angiogenesis and osteogenesis in vivo. We designed a porous titanium alloy scaffold/thermosensitive collagen hydrogel system, equipped with VEGF, to promote local osseointegration and angiogenesis. We also verified the VEGF release via thermosensitive collagen and proliferation and induction of the human umbilical vein endothelial cells (HUVECs) via the composite system in vitro. In vivo, using microscopic computed tomography (Micro-CT), histology, and immunohistochemistry analysis, we confirmed that the composite scaffold aids in angiogenesis-mediated bone regeneration, and promotes significantly more bone integration. We also discovered that the composite scaffold has excellent biocompatibility, provides bioactive VEGF for angiogenesis and osteointegration, and provides an important theoretical basis for the restoration of local blood supply and strengthening of bone integration.

Soft X-Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy.

Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep-seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X-ray activated nanoprobe is rationally engineered via integrating porphyrin Zr-based metal-organic framework with lanthanide NaYF4 :Gd,Tb@NaYF4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X-ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X-ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune-response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X-ray triggered deep-tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.

Low Dose Soft X-Ray Remotely Triggered Lanthanide Nanovaccine for Deep Tissue CO Gas Release and Activation of Systemic Anti-Tumor Immunoresponse.

Gas-based therapy has emerged as a new green therapy strategy for anti-tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X-ray-triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF4 :Gd,Tb@NaLuF4 ) with photo-responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno-therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X-ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti-tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X-ray activated systemic anti-tumor immunoresponse. This work provides a new strategy of designing anti-tumor nanovaccines for synergistic deep tissue gas-therapy and remote soft X-ray photoactivation of the immune response.