Declines in male reproductive capacity caused by ionizing radiation (IR) have emerged as an urgent clinical challenge, posing a serious threat to male fertility and overall reproductive health. In this study, we first elucidated that such damage arises from radiation-induced abscopal effects, in which S100A4+ macrophages drive oxidative phosphorylation reactive oxygen species (OXPHOS-ROS) signaling to impair testicular interstitial cells. To address this, a novel ROS-responsive nanoplatform was engineered to synergistically exert antioxidant effects and precisely inhibit OXPHOS, thereby repairing IR-induced testicular injury. This platform integrates the antioxidant tannic acid (TA) and the OXPHOS inhibitor metformin (MET) into drug-loaded microspheres (HA-TAMET) via dynamic crosslinking with phenylboronic acid-modified hyaluronic acid (HA-PBA), enabling targeted and controlled drug release within ROS-enriched microenvironments. Mechanistic studies revealed that HA-TAMET selectively accumulates in the testis, effectively scavenges excessive ROS, suppresses S100A4+ macrophage activation, and restores Leydig cell steroidogenesis by reprogramming the OXPHOS-ROS axis. In vivo experiments demonstrated that HA-TAMET markedly attenuates IR-induced testicular fibrosis, preserves blood-testis barrier (BTB) integrity, and normalizes serum testosterone levels in irradiated mice. This work highlights a nanomaterial-based therapeutic strategy for mitigating radiation-associated abscopal damage and offers new perspectives for reproductive protection and immune-metabolic modulation.

BACKGROUND:Glioblastoma (GBM), a common type of brain tumor, is currently treatable through radiation therapy. However, there is room for improvement in the effectiveness of treatment. Radiation can lead to an increase in the expression of PD-L1 and VEGF, which might reduce the responsiveness of the tumor to the therapy. This situation underlines the necessity for innovative treatment strategies. OBJECTIVES:In this study, we investigated the potential of attenuated Salmonella carrying the co-expressing plasmid siPD-L1-Endo to effectively inhibit PD-L1 and VEGF expression, thereby enhancing the anti-tumor effects of radiation therapy in GBM-bearing mice. METHODS:The regulatory mechanisms responsible for the treatment effect were detected by Flow cytometry, Immunohistochemistry, TUNEL, Immunofluorescence, H&E staining, and Western blot assays. RESULTS AND DISCUSSION:Upon administration of attenuated Salmonella carrying siRNAPD- L1 and co-expressing endostatin plasmids, the results exhibited significant suppression of tumor growth and tumor cell proliferation, as well as a concurrent decrease in PD-L1 and VEGF expression in tumor tissues. Moreover, the treatment led to reduced expression levels of tumor-related proteins p-Stat3, MMP2, Cyclin D1, and PCNA, an increase in the expression of the apoptosis-related protein cleaved-caspase3, facilitated infiltration of CD4+ and CD8+ T cells within tumor tissues, and an elevation of the ratios of CD4+, CD8+ T cells, and NK cells in the spleen of tumor-bearing mice. CONCLUSION:These findings highlight the ability of attenuated Salmonella carrying siRNA- PD-L1 and co-expressing endostatin plasmids to effectively modulate PD-L1 and VEGF expression, thus strengthening the anti-tumor immune response in GBM-bearing mice subjected to radiation therapy. This combination therapy approach holds promise as a potential avenue for improving the efficacy of radiation therapy in the treatment of glioblastoma.

Nerve injury-induced protein 1 (NINJ1) is a multifunctional membrane protein historically studied for its roles in nerve regeneration and cell adhesion. A groundbreaking study fundamentally revised our understanding by demonstrating that NINJ1 acts as the active executor of plasma membrane rupture in lytic cell death pathways such as pyroptosis and ferroptosis, establishing this final step as a biologically regulated process. Recent structural insights now reveal that NINJ1 adopts distinct molecular forms-including the full-length monomer, a soluble fragment, and a membrane-rupturing oligomer-which dictate its functional roles in adhesion, chemotaxis, and cell lysis. This revised understanding calls for a systematic integration of previous observations, particularly given NINJ1's context-dependent and often contradictory roles in inflammation, cancer, and tissue injury. Here, we review the structural basis of NINJ1 function, its pathological implications, and propose a unified structure-function model to reconcile its diverse phenotypes and bridge its traditional roles with its newly identified function in membrane rupture.

Autophagy is an evolutionarily conserved process of cell self-catabolism that provides a minimum level of energy for cellular homeostasis during metabolic stress. In radiotherapy (RT), it has been explicitly explained that autophagy plays a dual role in tumour control by tuning cellular radiosensitivity. However, the underlying molecular mechanism remains a conundrum. Therefore, it is of utmost importance to gain insight into the molecular mechanisms elaborating the autophagy-mediated radiosensitivity and craft refined RT strategies for different tumours. Distinguishing it from previous reviews in the field, here we discuss the mechanisms of autophagy, especially its pro-survival and growth-suppressing mechanisms via regulation of radiosensitivity. We further outline some frontier RT adjuvant therapies targeting autophagy, in an endeavour to shed some light on the autophagy-mediated pathways to harness radiosensitivity.

High-energy neutron radiation (HENR) induces severe cellular and tissue damage, yet effective prophylactic agents remain limited. In this study, the TLR2/NOD2 co-agonist CL429 was evaluated for its radioprotective potential against 14.1 MeV neutron exposure. A murine HENR model was established, and absorbed doses were calculated using the specific kinetic energy method. Pretreatment with CL429 significantly improved survival outcomes, with survival rates reaching 90% and prolonged survival times observed. CL429 administration markedly increased the organ indices of the spleen, thymus, and testis, reduced splenocyte apoptosis to near-normal levels, and restored leukocyte and platelet counts in the early postirradiation phase. Flow cytometry and Western blot analyses indicated that CL429 upregulated TLR2 and NOD2 expression, accompanied by activation of downstream signaling pathways. These findings suggest that CL429 confers significant protection against neutron radiation-induced injury, potentially through the dual activation of TLR2/NOD2-mediated protective mechanisms.

OBJECTIVE:To explore the potential the role of miR-151a-5p in sperm dysfunction and its association with DNA fragmentation, mitochondrial dysfunction, and male infertility. METHODS:Sperm samples with high DNA fragmentation were collected, and miR-151a-5p expression was measured using quantitative polymerase chain reaction. GC-2 cells were transfected with miR-151a-5p mimics to assess its effects on DNA damage, apoptosis, mitochondrial function, and reactive oxygen species levels. RNA sequencing, RNA pull-down, and bioinformatics analyses were used to identify the direct target genes of miR-151a-5p. Dual-luciferase reporter assays confirmed the binding of miR-151a-5p to the 3' untranslated regions of INPP4B and VAMP1. Knockdown of these genes was performed to validate their roles in miR-151a-5p-induced effects. In vivo experiments were conducted by injecting miR-151a-5p mimics into mouse zygotes to examine the impact on embryo development. RESULTS:miR-151a-5p was significantly upregulated in sperm with high DNA fragmentation and negatively correlated with sperm motility and viability. Overexpression of miR-151a-5p in GC-2 cells was associated with increased DNA damage, apoptosis, mitochondrial dysfunction, and elevated reactive oxygen species. RNA sequencing and bioinformatics analyses suggested INPP4B and VAMP1 as direct targets of miR-151a-5p. Dual-luciferase assays confirmed that miR-151a-5p binds to their 3' untranslated regions, inhibiting their expression at both the messenger RNA and protein levels. Knockdown of INPP4B or VAMP1 partially reproduced the cellular changes observed with miR-151a-5p overexpression. In vivo, microinjection of miR-151a-5p mimics into mouse zygotes exerted only mild effects on embryo development, indicating a possible contribution of miR-151a-5p primarily through sperm dysfunction. CONCLUSIONS:miR-151a-5p may contributes to sperm dysfunction by targeting INPP4B and VAMP1, linking DNA fragmentation with mitochondrial and genomic instability. This study offers additional insights into the molecular mechanisms underlying male infertility.

Nuclear electromagnetic pulse (NEMP) as a public hygiene issue has aroused increasing attention. Recent research has demonstrated that NEMP can disrupt the male reproductive system. Molecular hydrogen, a selective hydroxyl radical scavenger, has been shown to have the protective effects against many diseases closely associated with oxidative damage. We sought to characterize the beneficial effects of molecular hydrogen on the male reproductive cells. GC-1 spermatogonial cells and TM-3 Leydig cells, two well-established male reproductive cell lines, were exposed to NEMP. Finally, we employed transcriptomic sequencing to explore the transcriptional changes in male reproductive cells induced by NEMP exposure. For the intervention, cells were incubated in hydrogen gas (H2 75%, O2 20%, and CO2 5%) for 1 h. NEMP exposure induced damage to both GC-1 and TM-3 cells, resulting in decreased cell viability and increased apoptosis rates. However, intervention with molecular hydrogen significantly mitigated this damage. Specifically, molecular hydrogen reduced the production of ROS and restored mitochondrial function, thereby alleviating oxidative stress and apoptosis. Transcriptomic sequencing analysis showed that NEMP affected the molecular function term antioxidant activity, particularly Gstp2, a gene predicted to be located in the mitochondria to promote glutathione transferase activity. Hence, molecular hydrogen is a promising protective agent against NEMP in the mechanism that other antioxidants cannot be available.

Radiation combined wound injury (RCWI) presents significant healing challenges due to radiation‐induced immune suppression, organ dysfunction, and disruption of growth factors and extracellular matrix dynamics. Conventional dressings like gauze are inadequate for these complex injuries. Hydrogels have emerged as a promising solution for radiation‐induced skin and mucosal injuries, offering superior mechanical strength, cell‐regeneration support, and multifunctional biochemical properties, including antimicrobial, antioxidant, and adhesive capabilities. They create a moist, biocompatible environment that promotes cell proliferation, migration, and tissue repair, while enabling sustained drug delivery, free radical scavenging, inflammation suppression, and Deoxyribonucleic acid (DNA） repair. Despite their potential, a systematic comparison of wound dressings for radiation injuries remains lacking. This review addresses this gap by focusing on multifunctional hydrogels as supportive matrices and therapeutic enhancers, exploring radiation‐impaired healing mechanisms, highlighting hydrogel advancements, and comparing their efficacy in common versus radiation‐induced wounds. It also provides future research directions and clinical practice insights, emphasizing the potential of hydrogels in RCWI treatment. By bridging current knowledge gaps, this review aims to guide future research and improve clinical practices in radiology and trauma medicine.

PURPOSE:Ionizing radiation (IR) has been shown to induce epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs), which is a critical cause of radiation-induced pulmonary fibrosis (RIPF). In this study, we investigated the role and molecular mechanisms of musashi2 (MSI2), an RNA-binding protein, in IR-induced EMT of AECs for aiming at potential therapeutic strategies to prevent RIPF. MATERIALS AND METHODS:Changes in the expression levels of MSI2 and EMT markers (E-cadherin, N-cadherin, and Vimentin) induced by IR in AECs were detected by western blot (WB). Then, the effect of MSI2 on IR-induced EMT of AECs was investigated by observing morphological changes and detecting expression of MSI2 and EMT markers by WB and immunofluorescence (IF). RNA-Seq analysis, WB and RT-qPCR were used to identify the targets of MSI2. RESULTS:We observed that IR could cause a significant increase of MSI2 protein expression, a down-regulation of E-cadherin and an up-regulation of Vimentin and N-cadherin in AECs (MLE-12 and RLE-6TN cells). We also revealed that MSI2 was involved in regulating the alteration of morphology and EMT-related markers in AECs after irradiation, suggesting the occurrence of EMT regulated by MSI2. Moreover, we found the mechanism of MSI2 participating in EMT by regulating the expression of transcription factor ZEB1, acting as a downstream target of MSI2 in IR-induced EMT of AECs. CONCLUSIONS:Our study unveils the critical role of MSI2 in IR-induced EMT of AECs and preliminarily elucidates its molecular mechanisms, providing new insights into the process of IR-induced pulmonary fibrosis.

Promoting the maturation of dendritic cells (DCs) play crucial roles in the effectiveness of activating of adaptive immune response. However, the immunosuppressive tumor microenvironments (TME) are thought to impede DC maturation and inhibit antigen presentation, significantly reducing the therapeutic efficacy of immunotherapy. Herein, to realize the cascade activation of DC maturation, we report the first time the integration of reactive oxygen species (ROS)/ferroptosis-mediated immunogenic cell death (ICD) effect, cGAS-STING activation, and tumor-specific delivery of immune adjuvants. To demonstrate this technique, we utilized FDA-approved hollow Prussian Blue (HPB) with good sonodynamic and chemodynamic activities as the template for the self-assembly of Mn-R837. HPB/Mn-R837 not only possesses enhanced US-activated ROS generation capability owing to the construction of heterojunctions, but also exhibits TME-responsive degradation behaviors, achieving the tumorspecific release of Fe2 +, Fe3+, Mn2+, Mn4+, and R837. HPB/Mn-R837-triggered cascade activation of DC maturation were elucidated, including (1) heterojunction fabrication, GSH consumption, and in-situ CDT coamplified ROS generation as well as ferroptosis could significantly induce robust ICD effect; (2) activation of the cGAS-STING pathway by the released Mn2+ serves to stimulate DC maturation; (3) direct promotion of DC maturation can be achieved by the tumor-specific released R837. As a result, significant antitumor effects have been discovered to completely eradicate primary tumors and effectively inhibit the growth of distant tumors without side effects. This work establishes a novel strategy for the integration of ROS/ferroptosis-induced ICD effect, STING activation, and tumor-specific delivery of immune adjuvants into a single nanostructure for establishing lasting and effective immune responses.

Ionizing radiation (IR) injuries are featured as acute radiation syndrome (ARS) and localized combined radiation-wound injury (CRWI). While scavenging reactive oxygen species (ROS) is a key strategy for mitigating IRinduced damage, the development of effective marine natural biomaterials for treatment remains rare and challenging. In this study, we engineered cuttlefish melanin nanoparticles (CMNs) and incorporated them into a poly (vinyl alcohol) (PVA) and sodium alginate (SA) matrix, enabling the in situ synthesis of PVA/SA@CMNs (PS@CMNs) hydrogels with multifaceted therapeutic benefits. CMNs pretreatment significantly alleviated radiation-induced damage in ARS models, particularly by protecting the hematopoietic and immune systems. Furthermore, PS@CMNs hydrogels exhibited exceptional antioxidant, photothermal antibacterial, and biodegradable properties than CMNs. Upon near-infrared laser irradiation, these hydrogels accelerated the healing of bacteria-infected CRWI. The therapeutic mechanism involves the regulation of apoptosis-related proteins, including Bax and Bcl-2, effectively inhibiting the apoptotic process. This study highlights the dual-action potential of CMNs and PS@CMNs hydrogels in mitigating radiation damage and promoting wound healing, offering a promising marine biomaterial-based approach for radiation protection and regenerative medicine.

Sonodynamic therapy (SDT) as a promising non-invasive anti-tumor means features the preferable penetration depth, which nevertheless, usually can't work without sonosensitizers. Sonosensitizers produce reactive oxygen species (ROS) in the presence of ultrasound to directly kill tumor cells, and concurrently activate anti-tumor immunity especially after integration with tumor microenvironment (TME)-engineered nanobiotechnologies and combined therapy. Current sonosensitizers are classified into organic and inorganic ones, and current most reviews only cover organic sonosensitizers and highlighted their anti-tumor applications. However, there have few specific reviews that focus on inorganic sonosensitizers including their design principles, microenvironment regulation, etc. In this review, inorganic sonosensitizers are first classified according to their design rationales rather than composition, and the action rationales and underlying chemistry features are highlighted. Afterward, what and how TME is regulated based on the inorganic sonosensitizers-based SDT nanoplatform with an emphasis on the TME targets-engineered nanobiotechnologies are elucidated. Additionally, the combined therapy and their applications in non-cancer diseases are also outlined. Finally, the setbacks and challenges, and proposed the potential solutions and future directions is pointed out. This review provides a comprehensive and detailed horizon on inorganic sonosensitizers, and will arouse more attentions on SDT. Inorganic sonosensitizers according to their design rationales rather than composition, and highlighted the action rationales and underlying chemistry features are summarized, wherein design principles are highlighted, followed by elucidations on tumor microenvironment-engineered inorganic sonosensitizers and combined therapy, for cancer and non-cancer applications.image

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide. Radiotherapy is the main component of LC treatment; however, its efficacy is often limited by radioresistance development, resulting in unsatisfactory clinical outcomes. Here, we found that LC radiosensitivity is up-regulated by decreased expression of long-chain acyl-CoA synthase 6 (ACSL6) after irradiation. Deletion of ACSL6 results in significant elevation of Friend leukemia integration 1 transcription factor (FLI1) and a marked decline of collagens (COLs). Blocking of ACSL6 impairs the tumor growth and upregulates FLI1, which reduces the levels of COLs and compromises irradiation-induced autophagy, leading to considerable therapeutic benefits during radiotherapy. Moreover, the direct interaction between ACSL6 and FLI1 and engagement between FLI1 and COLs indicates the involvement of the ACSL6-FLI1-COL axis. Finally, the potently adjusted autophagy flux reduces its otherwise contributive capability in surviving irradiation stress and leads to satisfactory radiosensitization for LC radiotherapy. These results demonstrate that enhanced ACSL6 expression promotes the aggressive performance of irradiated LC through increased FLI1-COL-mediated autophagy flux. Thus, the ACSL6-FLI1-Col-autophagy axis may be targeted to enhance the radiosensitivity of LC and improve the management of LC in radiotherapy.

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth. However, the inevitable accumulation of sonosensitizers in normal tissues not only make it difficult to realize the in situ SDT, but also induces sonodynamic effects in normal tissues. Herein, this work reports the passivation and selective activation strategies for the sonodynamic and near-infrared (NIR) imaging performances of an intelligent antitumor theranostic platform termed Cu-IR783 nanoparticles (NPs). Owing to the ruptured coordination bond between IR783 with Cu ions by responding to tumor microenvironment (TME), the selective activation of IR783 only occurred in tumor tissues to achieve the visualized in-situ SDT. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu+-mediated Fenton-like reaction, but also triggered cuproptosis through Cu+-induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a distinct paradigm of the integration of SDT, CDT, and cuproptosis in a controlled manner to achieve visualized in-situ antitumor therapy.

Postoperative adhesion is a common post-surgery complication formed between the surface of the body cavity, ranging from a layer of connective tissue to a fibrous bridge containing blood vessels and nerve tissue. Despite achieving a lot of progress, the mechanisms of adhesion formation still need to be further studied. In addition, few current treatments are consistently effective in the prevention of postoperative adhesion. Hydrogel is a kind of water-expanding crosslinked hydrophilic polymer network generated by a simple reaction of one or more monomers. Due to the porous structure, hydrogels can load different drugs and control the drug release kinetics. Evidence from existing studies has confirmed the feasibility and superiority of using hydrogels to counter postoperative adhesions, primarily due to their outstanding antifouling ability. In this review, the current research status of hydrogels as anti-adhesion barriers is summarized, the character of hydrogels in the prevention of postoperative adhesion is briefly introduced, and future research directions are discussed.

Figure S1. DAB2IP expression does not affect key repair factors in NHEJ (Ku70, Ku80) and HR (RAD51, BRCA1) and PARP-1 mRNA expression. Figure S2. RANBP2, TRIP12, and RNF40 interact with both DAB2IP and PARP-1. Figure S3. Radiotherapy of RCC xenograft models.

BackgroundExcessive doses of electromagnetic radiation pose a negative impact on the central nervous system and lead to mental disorders. Molecular hydrogen can scavenge intracellular hydroxyl radicals, acting as an antioxidant, anti-apoptotic and anti-inflammatory agent. We seek to assess the capability of molecular hydrogen to ameliorate brain damage induced by electromagnetic radiation.MethodsNEMP (nuclear electromagnetic pulse), a subset of electromagnetic pulse with high voltage value that could cause severe brain injury, was applied to this study. Male wild-type rats were divided into four groups: the control group, the H2 (Molecular hydrogen) group, the NEMP group and the NEMP+H2 group. Rats in the H2 group and the NEMP+H2 group were fed with saturated hydrogen-rich water from 3 days before NEMP exposure (electromagnetic field intensity 400 kV/m, rising edge 20 ns and pulse width 200 ns) to the day of sacrifice. One day after exposure, animal behavior experiments were performed, and samples for transcriptomics and metabolomics analysis were collected. Seven days after exposure, histopathological experiments were conducted.ResultsThe data from the elevated plus maze and the open field test showed that NEMP exposure elicited anxiety-like behavior in rats, which could be alleviated by H2 treatment. Histopathological results manifested that NEMP exposure-induced injuries of the neurons in the hippocampus and amygdala could be attenuated by H2 treatment. Transcriptomic results revealed that NEMP exposure had a profound effect on microtubule structure in the brain. And the combined analysis of transcriptomics and metabolomics showed that H2 has a significant impact on the neuroactive ligand-receptor interaction, synaptic vesicle cycle and synapse etc. Moreover, it was indicated that the glutathione metabolic pathway played a vital role in the NEMP exposure-induced damage and the protective activity of H2.ConclusionsH2 is identified as a potent agent against NEMP exposure-induced brain damage and has the potential to be a promising electromagnetic radiation protectant.

BackgroundAcquired radio-resistance and the undesired normal tissue radiation injuries seriously discount the therapeutic effect of lung cancer radiotherapy. In this study, we aimed to explore the role and potential mechanism of polydatin in simultaneously decreasing radioresistance and radiation injuries.MethodsThe tumor-bearing model of nude mice was used to investigate the tumor inhibition of polydatin on lung cancer and its effect on radiosensitivity, and the effect of polydatin on B cell infiltration in cancerous tissue was investigated. In addition, we performed systemic radiotherapy on BABL/C mice and evaluated the protective effect of polydatin on radiation injury by the Kaplan-Meier survival curve. Moreover, the regulation of polydatin on proliferation and apoptosis of A549 cells was also investigated in vitro.ResultsIn this study, it is first found that polydatin inhibits the growth and promotes the radiosensitivity of lung cancer while reducing the radiation damage of the healthy tissue. Further, it is evidenced that the major mechanism relies on its regulation on body's immune function, and in particular, the inhibition of radiation-induced B cell infiltration in tumor tissue.ConclusionThese findings show that in addition to tumor inhibition, polydatin also promotes the sensitivity and reduces the adverse reactions of radiotherapy, making itself a promising candidate for boosting lung cancer radiotherapy efficacy.

Ionizing radiation (IR) poses a growing threat to human health, and thus ideal radioprotectors with high efficacy and low toxicity still receive widespread attention in radiation medicine. Despite significant progress made in conventional radioprotectants, high toxicity, and low bioavailability still discourage their application. Fortunately, the rapidly evolving nanomaterial technology furnishes reliable tools to address these bottlenecks, opening up the cutting-edge nano-radioprotective medicine, among which the intrinsic nano-radioprotectants characterized by high efficacy, low toxicity, and prolonged blood retention duration, represent the most extensively studied class in this area. Herein, we made the systematic review on this topic, and discussed more specific types of radioprotective nanomaterials and more general clusters of the extensive nano-radioprotectants. In this review, we mainly focused on the development, design innovations, applications, challenges, and prospects of the intrinsic antiradiation nanomedicines, and presented a comprehensive overview, in-depth analysis as well as an updated understanding of the latest advances in this topic. We hope that this review will promote the interdisciplinarity across radiation medicine and nanotechnology and stimulate further valuable studies in this promising field.