An Engineered Nanoplatform with Tropism toward Irradiated Glioblastoma Augments Its Radioimmunotherapy Efficacy.

Combining radiotherapy with immune checkpoint blockade therapy offers a promising approach to treat glioblastoma multiforme (GBM), yet challenges such as limited effectiveness and immune-related adverse events (irAEs) persist. These issues are largely due to the failure in targeting immunomodulators directly to the tumor microenvironment. To address this, we developed a biomimetic nanoplatform that combines a genetically modified mesenchymal stem cell (MSC) membrane with a bioactive nanoparticle core for chemokine-directed radioimmunotherapy of GBM. The CCR2-overexpressing MSC membrane acts as a tactical tentacle to achieve radiation-induced tropism toward the abundant chemokine ligand CCL2 in irradiated gliomas. The nanoparticle core, comprising diselenide-bridged mesoporous silica nanoparticles (MSNs) and PD-L1 antibodies (αPD-L1), enables X-ray-responsive drug release and radiosensitization. In two murine models with orthotopic GBM tumors, this nanoplatform reinvigorated immunogenic cell death, and augmented the efficacy and specificity of GBM radioimmunotherapy, with reduced occurrence of irAEs. This study suggests a promising radiation-induced tropism strategy for targeted drug delivery, and presents a potent nanoplatform that enhances the efficacy and safety of radio-immunotherapy. This article is protected by copyright. All rights reserved.

[Breast cancer lesion segmentation based on co-learning feature fusion and Transformer].

The PET/CT imaging technology combining positron emission tomography (PET) and computed tomography (CT) is the most advanced imaging examination method currently, and is mainly used for tumor screening, differential diagnosis of benign and malignant tumors, staging and grading. This paper proposes a method for breast cancer lesion segmentation based on PET/CT bimodal images, and designs a dual-path U-Net framework, which mainly includes three modules: encoder module, feature fusion module and decoder module. Among them, the encoder module uses traditional convolution for feature extraction of single mode image; The feature fusion module adopts collaborative learning feature fusion technology and uses Transformer to extract the global features of the fusion image; The decoder module mainly uses multi-layer perceptron to achieve lesion segmentation. This experiment uses actual clinical PET/CT data to evaluate the effectiveness of the algorithm. The experimental results show that the accuracy, recall and accuracy of breast cancer lesion segmentation are 95.67%, 97.58% and 96.16%, respectively, which are better than the baseline algorithm. Therefore, it proves the rationality of the single and bimodal feature extraction method combining convolution and Transformer in the experimental design of this article, and provides reference for feature extraction methods for tasks such as multimodal medical image segmentation or classification.

Evaluation of intramural hematoma: a novel use of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging.

BACKGROUND: Aortic intramural hematoma (IMH) is one of the typical entities of acute aortic syndrome and probably accounts for 5-25% of all cases. The ulcer-like projections (ULP), which are described as a focal, blood-filled pouch protruding into the hematoma of the aortic wall, are regarded as one of the high-risk imaging features of IMH and may cause initial medical treatment failure and death. CASE PRESENTATION: We present a case report of an acute type B IMH patient with impaired renal function and newly developed ULP in the acute phase. The 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MR) was performed to evaluate the condition of aortic hematoma. The 18F-FDG focal uptake along the aortic wall of the hematoma was normal compared to the background (SUVmax 2.17; SUVSVC 1.6; TBR 1.35). We considered the IMH stable in such cases and opted for medical treatment and watchful observation. Six months after discharge, the patient's recovery was satisfactory, and aortic remodeling was ideal. CONCLUSIONS: The 18F-FDG PET/MR is a novel tool to evaluate the risk of IMH patients and thus provides information for therapy selection.

3D Printing of a Vascularized Mini-Liver Based on the Size-Dependent Functional Enhancements of Cell Spheroids for Rescue of Liver Failure.

The emerging stem cell-derived hepatocyte-like cells (HLCs) are the alternative cell sources of hepatocytes for treatment of highly lethal acute liver failure (ALF). However, the hostile local environment and the immature cell differentiation may compromise their therapeutic efficacy. To this end, human adipose-derived mesenchymal stromal/stem cells (hASCs) are engineered into different-sized multicellular spheroids and co-cultured with 3D coaxially and hexagonally patterned human umbilical vein endothelial cells (HUVECs) in a liver lobule-like manner to enhance their hepatic differentiation efficiency. It is found that small-sized hASC spheroids, with a diameter of ≈50 µm, show superior pro-angiogenic effects and hepatic differentiation compared to the other counterparts. The size-dependent functional enhancements are mediated by the Wnt signaling pathway. Meanwhile, co-culture of hASCs with HUVECs, at a HUVECs/hASCs seeding density ratio of 2:1, distinctly promotes hepatic differentiation and vascularization both in vitro and in vivo, especially when endothelial cells are patterned into hollow hexagons. After subcutaneous implantation, the mini-liver, consisting of HLC spheroids and 3D-printed interconnected vasculatures, can effectively improve liver regeneration in two ALF animal models through amelioration of local oxidative stress and inflammation, reduction of liver necrosis, as well as increase of cell proliferation, thereby showing great promise for clinical translation.

Few-shot segmentation framework for lung nodules via an optimized active contour model.

BACKGROUND: Accurate segmentation of lung nodules is crucial for the early diagnosis and treatment of lung cancer in clinical practice. However, the similarity between lung nodules and surrounding tissues has made their segmentation a longstanding challenge. PURPOSE: Existing deep learning and active contour models each have their limitations. This paper aims to integrate the strengths of both approaches while mitigating their respective shortcomings. METHODS: In this paper, we propose a few-shot segmentation framework that combines a deep neural network with an active contour model. We introduce heat kernel convolutions and high-order total variation into the active contour model and solve the challenging nonsmooth optimization problem using the alternating direction method of multipliers. Additionally, we use the presegmentation results obtained from training a deep neural network on a small sample set as the initial contours for our optimized active contour model, addressing the difficulty of manually setting the initial contours. RESULTS: We compared our proposed method with state-of-the-art methods for segmentation effectiveness using clinical computed tomography (CT) images acquired from two different hospitals and the publicly available LIDC dataset. The results demonstrate that our proposed method achieved outstanding segmentation performance according to both visual and quantitative indicators. CONCLUSION: Our approach utilizes the output of few-shot network training as prior information, avoiding the need to select the initial contour in the active contour model. Additionally, it provides mathematical interpretability to the deep learning, reducing its dependency on the quantity of training samples.

Emerging nanoparticle platforms for CpG oligonucleotide delivery.

Unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs), which were therapeutic DNA with high immunostimulatory activity, have been applied in widespread applications from basic research to clinics as therapeutic agents for cancer immunotherapy, viral infection, allergic diseases and asthma since their discovery in 1995. The major factors to consider for clinical translation using CpG motifs are the protection of CpG ODNs from DNase degradation and the delivery of CpG ODNs to the Toll-like receptor-9 expressed human B-cells and plasmacytoid dendritic cells. Therefore, great efforts have been devoted to the advances of efficient delivery systems for CpG ODNs. In this review, we outline new horizons and recent developments in this field, providing a comprehensive summary of the nanoparticle-based CpG delivery systems developed to improve the efficacy of CpG-mediated immune responses, including DNA nanostructures, inorganic nanoparticles, polymer nanoparticles, metal-organic-frameworks, lipid-based nanosystems, proteins and peptides, as well as exosomes and cell membrane nanoparticles. Moreover, future challenges in the establishment of CpG delivery systems for immunotherapeutic applications are discussed. We expect that the continuously growing interest in the development of CpG-based immunotherapy will certainly fuel the excitement and stimulation in medicine research.

Urinary Endometriosis Misdiagnosed as Ureteral Malignant Tumor by PET/CT: A Case Study.

ABSTRACT: Endometriosis is a chronic inflammatory estrogen-dependent benign disease. It is defined as the endometrium growing outside the uterine cavity and the myometrium. It usually has low FDG uptake but rarely occurs in the ureters. We reported a case of a 47-year-old woman's left ureteral nodule originally misdiagnosed as a ureteral malignant tumor by PET/CT and finally pathologically confirmed as endometriosis.

Leveraging Radiation-triggered Metal Prodrug Activation Through Nanosurface Energy Transfer for Directed Radio-chemo-immunotherapy.

Metal-based drugs currently dominate the field of chemotherapeutic agents; however, achieving the controlled activation of metal prodrugs remains a substantial challenge. Here, we propose a universal strategy for the radiation-triggered activation of metal prodrugs via nanosurface energy transfer (NSET). The core-shell nanoplatform (Ru-GNC) is composed of gold nanoclusters (GNC) and ruthenium (Ru)-containing organic-inorganic hybrid coatings. Upon X-ray irradiation, chemotherapeutic Ru (II) complexes were released in a controlled manner through a unique NSET process involving the transfer of photoelectron energy from the radiation-excited Ru-GNCs to the Ru-containing hybrid layer. In contrast to the traditional radiation-triggered activation of prodrugs, such an NSET-based system ensures that the reactive species in the tumor microenvironment are present in sufficient quantity and are not easily quenched. Additionally, ultrasmall Ru-GNCs preferably target mitochondria and profoundly disrupt the respiratory chain upon irradiation, leading to radiosensitization by generating abundant reactive oxygen species. Consequently, Ru-GNC-directed radiochemotherapy induces immunogenic cell death, resulting in significant therapeutic outcomes when combined with the programmed cell death-ligand 1 (PD-L1) checkpoint blockade. This NSET strategy represents a breakthrough in designing radiation-triggered nanoplatforms for metal-prodrug-mediated cancer treatment in an efficient and controllable manner.

A comprehensive predictive model for radiation-induced brain injury in risk stratification and personalized radiotherapy of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.

Autoantibody repertoire profiling in tissue and blood identifies colorectal cancer-specific biomarkers.

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.

Intravenous Senescent Erythrocyte Vaccination Modulates Adaptive Immunity and Splenic Complement Production.

Targeted delivery of vaccines to the spleen remains a challenge. Inspired by the erythrophagocytotic process in the spleen, we herein report that intravenous administration of senescent erythrocyte-based vaccines profoundly alters their tropism toward splenic antigen-presenting cells (APCs) for imprinting adaptive immune responses. Compared with subcutaneous inoculation, intravenous vaccination significantly upregulated splenic complement expression in vivo and demonstrated synergistic antibody killing in vitro. Consequently, intravenous senescent erythrocyte vaccination produces potent SARS-CoV-2 antibody-neutralizing effects, with potential protective immune responses. Moreover, the proposed senescent erythrocyte can deliver antigens from resected tumors and adjuvants to splenic APCs, thereby inducing a personalized immune reaction against tumor recurrence after surgery. Hence, our findings suggest that senescent erythrocyte-based vaccines can specifically target splenic APCs and evoke adaptive immunity and complement production, broadening the tools for modulating immunity, helping to understand adaptive response mechanisms to senescent erythrocytes better, and developing improved vaccines against cancer and infectious diseases.

Effect of low dose laser cycloplasty on deepening anterior chamber in chronic angle-closure glaucoma.

AIM: To describe the outcome of using low-dose laser cycloplasty (LCP) in chronic angle-closure glaucoma (CACG). METHODS: A retrospective case series. Medical charts of CACG patients who underwent LCP in the Eye Hospital of Wenzhou Medical University were reviewed. The main outcomes included intraocular pressure (IOP), the number of glaucoma medication, anterior segment parameters and surgery-related complications. RESULTS: A total of 7 eyes of 7 CACG patients (age 38.9±11.0y) underwent LCP with a mean follow-up of 27.1±13.7mo (range 16-48mo). Following LCP, mean IOP and glaucoma medications decreased from 26.1±6.1 mm Hg with 3.1±1.1 glaucoma medications pre-treatment to 14.9±3.1 mm Hg (P=0.027) with 0.4±1.1 glaucoma medications (P=0.001) at final follow-up. The anterior chamber depth (ACD), angle opening distance500 and trabecular-iris angle increased from 1.65±0.33 mm, 0.05 mm (range 0-0.30 mm) and 5.1° (range, 0-31.97°) at baseline to 1.98±0.43 mm (P=0.073), 0.53 mm (range 0.42-0.91 mm, P=0.015), 45.9° (range, 40.2°-59.4°, (P=0.015) in the long-term follow-up, respectively. The deepening of ACD and reopening of anterior chamber angle (ACA) was observed in 6 eyes (85.7%). CONCLUSION: LCP is a promising treatment option for patients with CACG via reducing IOP and glaucoma medication without serious complications. In addition, LCP can bring a significant deepening in ACD and reopening of ACA.

Dietary pyrroloquinoline quinone improvement of the antioxidant capacity of laying hens and eggs are linked to the alteration of Nrf2/HO-1 pathway and gut microbiota.

Pyrroloquinoline quinone disodium (PQQ·Na2) has been considered a human food supplement for human health promotion with its antioxidant properties. To determine whether PQQ·Na2 had similar functions to improve the antioxidant ability of layers and eggs, 180 laying hens were fed with 0 or 0.4 mg/kg PQQ·Na2 diets. Supplementation with PQQ·Na2 increased the albumen height, Haugh unit of the eggs. PQQ·Na2 also led to a higher glutathione peroxidase (GSH-Px) concentration in plasma and a lower malondialdehyde (MDA) content in the liver and egg yolk. Similarly, liver gene and protein expression of nuclear factor erythroid 2-related 2 (Nrf2) and heme oxygenase 1 (HO-1) were up-regulated by PQQ·Na2. Moreover, PQQ·Na2 increased the abundance of Firmicutes, Microbacterium, Erysipelatoclostridium, Mailhella, Lachnospiraceae_UCG-010, and Herbaspirillum in gut. Overall, these results suggested PQQ·Na2 increased the antioxidant ability of layers and eggs which might be in connection with the activation of the Nrf2/HO-1 pathway and optimized gut microflora.

Retracted: Long Noncoding RNA TP73-AS1 Targets MicroRNA-329-3p to Regulate Expression of the SMAD2 Gene in Human Cervical Cancer Tissue and Cell Lines.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Mei Mei Guan, Qun Xian Rao, Miao Ling Huang, Li Juan Wang, Shao Dan Lin, Qing Chen, Chang Hao Liu. Long Noncoding RNA TP73-AS1 Targets MicroRNA-329-3p to Regulate Expression of the SMAD2 Gene in Human Cervical Cancer Tissue and Cell Lines. Med Sci Monit, 2019; 25: 8131-8141. DOI: 10.12659/MSM.916292.

Cationic mesoporous silica nanoparticles alleviate osteoarthritis by targeting multiple inflammatory mediators.

Osteoarthritis (OA) is a common and complex inflammatory disorder that is frequently compounded by cartilage degradation, synovial inflammation, and osteophyte formation. Damaged chondrocytes release multiple danger mediators that exacerbate synovial inflammation and accelerate the progression to OA. Conventional treatments targeting only a single mediator of OA have failed to achieve a strong therapeutic effect. Addressing the crucial role of multiple danger mediators in OA progression, we prepared polyethylenimine (PEI)-functionalized diselenide-bridged mesoporous silica nanoparticles (MSN-PEI) with cell-free DNA (cfDNA)-binding and anti-oxidative properties. In models of surgery-induced and collagenase-induced arthritis, we showed that these cationic nanoparticles attenuated cartilage degradation and provided strong chondroprotection against joint damage. Mechanistically, multiple target blockades alleviated oxidative stress and dampened cfDNA-induced inflammation by suppressing the M1 polarization of macrophages. This study suggests a beneficial direction for targeting multiple danger mediators in the treatment of intractable arthritis.

Study on the Alleviating Effect and Potential Mechanism of Ethanolic Extract of Limonium aureum (L.) Hill. on Lipopolysaccharide-Induced Inflammatory Responses in Macrophages.

Inflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

Activation of Chaperone-Mediated Autophagy Inhibits the Aryl Hydrocarbon Receptor Function by Degrading This Receptor in Human Lung Epithelial Carcinoma A549 Cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a substrate protein of a Cullin 4B E3 ligase complex responsible for diverse cellular processes. In the lung, this receptor is responsible for the bioactivation of benzo[a]pyrene during tumorigenesis. Realizing that the AHR function is affected by its expression level, we are interested in the degradation mechanism of AHR in the lung. Here, we have investigated the mechanism responsible for AHR degradation using human lung epithelial A549 cells. We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent manner. Treatment with 6-aminonicotinamide (6-AN), a chaperone-mediated autophagy (CMA) activator, decreases AHR protein levels in a concentration-dependent and time-dependent manner. This decrease suppresses the ligand-dependent activation of the AHR target gene transcription, and can be reversed by CQ but not MG132. Knockdown of lysosome-associated membrane protein 2 (LAMP2), but not autophagy-related 5 (ATG5), suppresses the chloroquine-mediated increase in the AHR protein. AHR is resistant to CMA when its CMA motif is mutated. Suppression of the epithelial-to-mesenchymal transition in A549 cells is observed when the AHR gene is knocked out or the AHR protein level is reduced by 6-AN. Collectively, we have provided evidence supporting that AHR is continuously undergoing CMA and activation of CMA suppresses the AHR function in A549 cells.

Whipple Disease Misdiagnosed as Lymphoma by 18 F-FDG PET/CT: A Case Study.

ABSTRACT: Whipple disease is a rare disorder caused by infection with the gram-positive bacterium Tropheryma whipplei . It can invade various organs and systems of the whole body. This case report describes a patient with invasion of multiple lymph nodes throughout the body misdiagnosed as lymphoma by PET/CT.

X-ray-controllable release of carbon monoxide potentiates radiotherapy by ultrastable hybrid nanoreservoirs.

Carbon monoxide (CO) exhibits unique abilities in sensitizing cancer radiotherapy (RT). However, the development of a highly stable CO-delivery nanosystem with sustained CO release in tumor tissues and the prevention of CO leakage into normal tissues remains a challenge. Herein, an organic-inorganic hybrid strategy is proposed to create ultrastable CO nanoreservoirs by locking an unstable iron carbonyl (FeCO) prodrug in a stable mesoporous silica matrix. Different from traditional FeCO-loading nanoplatforms, FeCO-bridged nanoreservoirs not only tethered labile FeCO in the framework to prevent unwanted FeCO leakage, but also achieved sustained CO release in response to X-ray and endogenous H2O2. Importantly, FeCO-bridged nanoreservoirs exhibited the sequential release of CO and Fe2+, thereby performing highly efficient chemodynamic therapy. Such a powerful combination of RT, gas therapy, and chemodynamic therapy boosts robust immunogenic cell death, thus enabling the elimination of deeply metastatic colon tumors with minimal side effects. The proposed organic-inorganic hybrid strategy opens a new window for the development of stable nanoreservoirs for the on-demand delivery of unstable gases and provides a feasible approach for the sequential release of CO and metal ions from metal carbonyl complexes.