X-ray-triggered molecular switching promises remote control behind physical barriers, yet existing radioswitches typically require multi-gray doses to reach a photostationary state. Here we route X-ray energy through triplet excitons to enable low-dose switching. An efficient scintillator acts as a triplet sensitizer, transferring energy to a photoswitch with lower triplet energy via triplet-triplet energy transfer (TTET). Flexible films combining a Cu2I2(POP)2 scintillator with hydrazone switch 1-I reach a photostationary state at ~0.18 Gy and show a detection limit near 0.01 mGy, about two orders of magnitude lower than previous systems. HPLC quantification, radical-scavenger tests, and time-resolved spectroscopy support a TTET-dominated mechanism and establish a design rule based on triplet-level matching. Isomerization quenches fluorescence, enabling optical readout for high-resolution radiography (3251 dpi) with pattern retention for at least two months. In this work, we show that penetrating X-rays enable practical control of molecular functions in previously inaccessible complex environments.

Spinal cord injury (SCI) is an irreversible neurological injury that leads to severe motor dysfunction and neurological deficiencies, imposing a large social load. Due to the difficulty of the SCI procedure, the prognosis is normally bad. In recent years, naturally derived hydrogels have garnered increasing attention. Peach gum (PG) primarily consists of macromolecular polysaccharides with abundant hydroxyl and carboxyl groups on its branched chains, making it amenable to modification. This study is the first to prepare carboxymethylated peach gum polysaccharide (CPG) using PG as the raw material and load it with nerve growth factor (NGF) to improve the adverse microenvironment post-SCI and promote axonal regeneration. Carboxymethylation modification of PG was done, and its effective change was verified by infrared spectroscopy and degree of replacement measurements. After loading NGF, its characterization was examined. The mechanical characteristics, thermal behavior, and self-healing ability of CPG + NGF were shown to be outstanding in the results. Cell experiments demonstrated that, compared to the sham-operated group, CPG + NGF significantly promotes neurite outgrowth and development in PC-12 cells. Ultimately, CPG + NGF was implanted into the injured spinal cords of rats, and research demonstrated that CPG + NGF significantly improves the microenvironment of the affected areas, fosters axonal regeneration in severely damaged spinal cord regions, and enhances motor function in the rats. The modified PG biopolymer scaffold developed in this study exhibits superior mechanical strength, excellent cytocompatibility, and enhanced biological functionality. In summary, this research provides new insights into the application of biomacromolecules in SCI repair.

Although photoluminescence imaging‐guided photodynamic therapy (PDT) is promising for theranostics, it easily suffers from tissue autofluorescence and PDT photoproducts. To develop time‐resolved imaging (TRI)‐guided PDT with long‐lived emission pathways, like thermally activated delayed fluorescence (TADF), is urgent but challenging, because of the triplet competition between radiative transition and reactive oxygen species (ROS) production. Herein, skeleton‐homologous nanoparticles are designed and constructed to address this dilemma, thereby achieving in vivo TRI‐guided PDT for the first time. This system is formed with a lipophilic TADF core (as a TRI probe) encapsulated by an amphiphilic photosensitizer shell (as the corona exposed to oxygen for PDT), both of which are derived from the same donor–acceptor skeleton to minimize phase separation in the single entity, and enable the same long‐wavelength photoexcitation for TRI and PDT. The chloropropylamine group is helpful for endoplasmic reticulum targeting to enhance PDT upon minimizing the ROS transmission path. Synchronously, the TADF core exhibits a delayed fluorescence of 40 µs for a clear TRI. The NPs are eventually applied in vivo with a high signal‐to‐background ratio (45.25) and outstanding PDT effects in a mouse model of deep‐seated kidney cancer. Such a material design is beneficial for developing high‐efficient and high‐contrast theranostic approaches.

Photodynamic therapy (PDT) faces challenges in hypoxic tumors due to oxygen-dependent type II mechanisms. Type I PDT, generating oxygen-free radicals, offers a promising alternative but requires efficient photosensitizers. Herein, we report a series of cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3 and Ir4) incorporating electron-rich conjugated C^N ligands and an electron-deficient N^N ligand (1,4,5,8-tetraazaphenanthrene, TAP). The synergistic interplay between these ligands enables a pump-like mechanism under photoexcitation, efficiently shuttling electrons to electron-accepting substrates while replenishing electrons from reducing donors, thereby driving robust reactive oxygen free radical generation. These complexes exhibit strong visible-light absorption, near-infrared luminescence with decent quantum efficiency, and effective type I & II PDT activity under hypoxia. In vitro and in vivo studies demonstrate negligible dark toxicity and exceptional phototoxicity upon visible-light irradiation. This work highlights a rational ligand-cooperative design strategy for metal complex-based type I photosensitizers, overcoming hypoxia limitations in conventional PDT while integrating traceable luminescence for potential clinical applications.

Fluorogenic bioorthogonal probes are crucial tools in biomedical research, which enable non-invasive, wash-free imaging of specific biomolecules in living systems. Lifetime-responsive bioorthogonal probes represent another promising and attractive alternative, offering the potential for real-time, wash-free visualization of bioorthogonal labeling processes via photoluminescence lifetime imaging microscopy (PLIM). However, their widespread application is limited by the lack of suitable lifetime-responsive probes. Herein, a series of phosphorescent iridium(III) phenanthrolinedione complexes were reported. Intriguingly, upon bioorthogonal reaction with an α-angelica lactone derivative, the complexes exhibited remarkable emission responses in three distinct manners, which were found to correlate with the different emissive excited states of the complexes. Crucially, two of the complexes maintained similar emission intensity but exhibited significant emission lifetime elongation during labeling reactions, which facilitated simultaneous and discriminative visualization of the reacted and unreacted probes in cellular imaging without the need for washing steps. One of the complexes was used for organelle targeting and specific protein labeling through bioorthogonal reactions in living cells. The intracellular probe transportation and labeling dynamics were visualized and analyzed using PLIM. This work highlights the unique potential of lifetime-responsive iridium(III) complexes as powerful chemical tools for live-cell imaging and unveiling the spatiotemporal dynamics of biomolecules during bioorthogonal reactions.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to similar to 158.7 mu s) and high quantum yield (up to similar to 30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from similar to 0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (similar to 108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O-2), offering opportunities for precision imaging analysis in a hypoxic environment.

Abnormalities in ether lipid metabolism as well as the formation of neutrophil extracellular traps have recently been recognized as detrimental factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here we show that the lipid metabolism-related gene enoyl-CoA δ-isomerase 2 (ECI2) plays a tumor-suppressor role in CRC and is negatively associated with poor prognosis in CRC patients. We mechanistically demonstrate that ECI2 reduces ether lipid-mediated Interleukin 8 (IL-8) expression leading to decreased neutrophil recruitment and neutrophil extracellular traps formation for colorectal cancer suppression. In particular, ECI2 inhibits ether lipid production in CRC cells by inhibiting the peroxisomal localization of alkylglycerone phosphate synthase (AGPS), the rate-limiting enzyme for ether lipid synthesis. These findings not only deepen our understanding of the role of metabolic reprogramming and neutrophil interactions in the progression of CRC, but also provide ideas for identifying potential diagnostic markers and therapeutic targets for CRC.

BACKGROUND:Endoplasmic reticulum stress (ERS) could be a strategy for treating malignant tumors. Moreover, long noncoding RNAs (lncRNAs) can promote tumorigenesis and progression, and forecast the prognosis of cancers. Nevertheless, the prognostic value of ERS-related lncRNAs has not been reported in lung adenocarcinoma (LUAD). METHODS:The messenger RNA (mRNA), microRNA (miRNA) and lncRNA expression data related to LUAD were obtained in public databases (TCGA and GEO databases). Prognostic ERS-related differentially expressed lncRNAs (ERS-DELs) were obtained and used to build an ERS-related model by Cox regression analysis. Moreover, we further screened independent prognostic elements and built a nomogram. Furthermore, enrichment analysis of genes was conducted to investigate the functions. A lncRNA-miRNA-mRNA network was built to explore mechanism of lncRNAs. Finally, qRT-PCR was utilized to examine the expression levels of lncRNAs. RESULTS:30 ERS-DELs were identified, and an ERS-related signature was built based on AF131215.2, LINC00472, LINC01352, RP1-78O14.1, RP11-253E3.3, RP11-98D18.9, and SNHG12. Gene set enrichment analysis indicated that genes in the high-risk group were chiefly focused on the regulation of mRNA binding, and genes in the low-risk group were significantly focused on protein localization to cilia. A lncRNA-miRNA-mRNA network, containing 7 signature lncRNAs, 23 miRNAs, and 128 mRNAs, was also established. Eventually, quantitative real-time polymerase chain reaction was used to confirm that seven prognostic lncRNAs had a consistent expression with the analysis. CONCLUSIONS:An ERS-related signature containing seven prognostic lncRNAs was built, which offered new thinking concerning the role of ERS-related lncRNAs in LUAD.

Color-tunability RTP nanoprobes are achieved by doping mineral acids in an organic silicon scaffold through a cross-linking process. The as-prepared nanoprobes enable multiple imaging in live cells with high signal-to-background ratio.

BackgroundLung adenocarcinoma patients are often found to have developed bone metastases at the time of initial diagnosis. With the continuous development of technology, we have successfully entered the era of immunotherapy. This study aimed to determine the efficacy of immunotherapy in lung adenocarcinoma patients with bone metastases (LABM) through a multicenter retrospective analysis and to develop a novel tool to identify the population that could benefit most from immunotherapy.MethodsTo assess the impact of immunotherapy on LABM in terms of overall survival, we used analytical tools such as Kaplan-Meier analysis, Log-ranch test, and propensity score matching (PSM) method. A predictive model for constructing overall survival was constructed using Cox regression modeling. Based on this, we developed a risk classification system depicting Kaplan-Meier curves for subgroup analysis to determine the optimal beneficiary population for immunotherapy in different risk subgroups.ResultsA total of 20073 eligible patients were enrolled in this study, of whom 8010 did not receive immunotherapy, while 12063 patients received immunotherapy. After 1:1 PSM, 15848 patients were successfully coordinated, yielding a balanced cohort. Kaplan-Meier survival curves showed significantly enhanced overall survival (P < 0.001) in patients who received immunotherapy compared to those who did not. The results of Cox regression analyses showed that age, race, sex, primary site, immunotherapy, surgery, chemotherapy, brain metastasis, liver metastasis, lung metastasis, and marital status were independent prognostic factors. The area under the curve for all three cohorts was close to 0.7, indicating that the model was well-discriminating. The calibration curves further proved that the model had a high predictive accuracy. Decision curve analysis demonstrated that the model could achieve a high net clinical benefit. The risk classification system developed based on the model successfully screened the best beneficiary population for immunotherapy.ConclusionThis study provides convincing evidence that immunotherapy provides a significant survival advantage for LABM. Secondly, the clinical tools constructed in this study can help clinicians identify the optimal population to benefit from immunotherapy in LABM, thus enabling precise treatment and avoiding the waste of medical resources and over-treatment of patients.

Persistent room temperature phosphorescent materials with unique mechanical properties and robust optical properties have great potential in flexible electronics and photonics. However, developing such materials remains a formidable challenge. Here, we present highly stretchable, lightweight, and multicolored persistent luminescence elastomers, produced by incorporating ionic room temperature phosphorescent polymers and polyvinyl alcohol into a polydimethylsiloxane matrix. These prepared elastomers exhibit high optical transparency in daylight and emit bright persistent luminescence after the removal of 365 nm excitation. The homogeneous distribution of polymers within the matrix has been confirmed by confocal fluorescence microscopy, scanning electron microscopy, and atomic force microscopy. Mechanical property investigations revealed that the prepared persistent luminescence elastomers possess satisfactory stretchability. Impressively, these elastomers maintain robust optical properties even under extensive and repeated mechanical deformations, a characteristic previously unprecedented. These fantastic features make these persistent luminescence elastomers ideal candidates for potential applications in wearable devices, flexible displays, and anti-counterfeiting.

Enzyme mimics (EMs) with intrinsic catalysis activity have attracted enormous interest in biomedicine. However, there is a lack of environmentally adaptive EMs for sensitive diagnosis and specific catalytic therapeutics in simultaneous manners. Herein, the coordination modulation strategy is designed to synthesize silicon-based phosphorescence enzyme-mimics (SiPEMs). Specifically, the atomic-level engineered Co-N4 structure in SiPEMs enables the environment-adaptive peroxidase, oxidase, and catalase-like activities. More intriguingly, the internal Si-O networks are able to stabilize the triplet state, exhibiting long-lived phosphorescence with lifetime of 124.5 ms, suitable for millisecond-range time-resolved imaging of tumor cells and tissue in mice (with high signal-to-background ratio values of ∼60.2 for in vitro and ∼611 for in vivo). Meanwhile, the SiPEMs act as an oxidative stress amplifier, allowing the production of ·OH via cascade reactions triggered by the tumor microenvironment (∼136-fold enhancement in peroxidase catalytic efficiency); while the enzyme-mimics can scavenge the accumulation of reactive oxygen species to alleviate the oxidative damage in normal cells, they are therefore suitable for environment-adaptive catalytic treatment of cancer in specific manners. We innovate a systematic strategy to develop high-performance enzymemics, constructing a promising breakthrough for replacing traditional enzymes in cancer treatment applications.

Abnormalities in ether lipid metabolism as well as neutrophil extracellular trap formation are recently identified as adverse factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here, we show that the lipid metabolism-related gene, enoyl-CoA delta isomerase 2 (ECI2), plays a tumor-suppressive role in CRC and is negatively associated with poor prognosis in CRC patients. Mechanistically, we demonstrate that ECI2 inhibits ether lipogenesis by restraining the peroxisomal localization of AGPS, the rate-limiting enzyme in ether lipid synthesis. This subsequently suppresses IL-8-mediated neutrophil recruitment and extracellular trap formation, ultimately leading to inhibition of CRC proliferation and metastasis. These findings not only enhance our comprehension of the role of metabolic reprogramming and neutrophil interactions in CRC development, but also offer novel insights for identifying potential diagnostic markers and therapeutic targets for CRC.

Photoresponsive materials have recently garnered significant research interest and have been designed using various molecules. A viable approach to develop photoresponsive materials is by integrating photoisomeric structures into the organic ligands of phosphorescent transition metal complexes. In this study, we designed two photoresponsive cyclometalating ligands, 2-phenyl-3-vinylpyridine (HL1) and trans-4-methyl-2-phenyl-3-styr-ylpyridine (HL2), via the replacement of a phenyl group with a pyridyl group in vinylbiphenyl. Upon photo -irradiation under an argon atmosphere, both ligands underwent photocyclization and demonstrated hypochromism and bathochromic shifts in absorption. Notably, HL2 underwent additional oxidative dehydro-genation upon photoirradiation in the presence of oxygen, resulting in an elongated conjugation structure that exhibited significant fluorescence intensity increase at 363 nm. Additionally, three photoresponsive iridium(III) complexes cyclometalated with HL1 or HL2 were synthesized and characterized. The photocyclization process of the complexes was much faster than that of the free ligands because the phenylpyridine moiety became coplanar upon cyclometalation. Upon photoirradiation under an argon atmosphere, these complexes exhibited significant luminescence enhancement by about 10-20 folds because of photocyclization resulting in a rigid closed structure that limited nonradiative decay of the excited complexes. These molecules present a unique strategy to construct photocyclization complexes and provide important insights into the development of photoresponsive materials.

Phosphorescent probes often show sensitive response toward analytes at a specific wavelength. However, oxygen quenching usually occurs at the same wavelength and thus hinders the accurate detection of analytes. In this study, we have developed dual-emissive iridium(III) complexes that exhibit phosphorescence responses to copper(II) ions at a wavelength distinct from that where oxygen quenching occurs. The complexes displayed colorimetric phosphorescence response in aqueous solutions under different copper(II) and oxygen conditions. In cellular imaging, variation in oxygen concentration over a large range from 5 % to 80 % can modulate the intensity and lifetime of green phosphorescence without affecting the response of red phosphorescence toward intracellular copper(II) ions.

Hypoxia of tumor microenvironments is a major factor restricting tumor treatment, which causes progression and metastasis of tumor. The hypoxic tumor microenvironment not only makes the traditional treatment method, such as chemotherapy, ineffective but also hinders the O2-dependent treatments, such as photodynamic therapy (PDT). Recently, stimuli-responsive nitric oxide (NO) donors have attracted extensive research interest in hypoxic tumor treatment because the NO release process is O2-independent. Besides, NO can distribute more uniformly than drug molecules and more widely than the PDT-generated active species due to its strong diffusion ability (200 μm in cells) and long lifetime (2 s in cells). Encouraged by these advantages, a near infrared light-triggered NO release polymeric nanoplatform (P1-CapNO NPs) was constructed by a thermally sensitive NO release unit, a photothermal unit, and a hydrophilic polyethylene glycol unit. P1-CapNO NPs possess strong absorption in the NIR region (the wavelength of maximal absorption peak was 790 nm with a molar absorption coefficient of 2.4 × 105 M-1 cm-1), great photothermal conversion efficiency (23.8%), and NO release ability (the released NO concentration can reach 1.3 μM) under 808 nm laser irradiation. Owing to these advantages, the great synergistic antitumor effect can be achieved in vitro and in vivo even under the hypoxic environment. The synergistic therapeutic strategy in this work could bypass the obstacles caused by hypoxia in tumor treatment and provide a reference for building a NO-involved therapeutic platform.

Background:As one of the most common malignant tumor, colorectal cancer (CRC) continues to have a high incidence and mortality rate. HRK belongs to the BCL-2 protein family, which has been shown to have antitumor effects in prostate cancer. However, its role in colorectal cancer is not yet known. Methods:In this study, we verified the expression levels of HRK in colorectal cancer tissues by public database search as well as immunohistochemistry. Next, we analyzed HRK expression levels in CRC tissues,adjacent non-cancerous tissues, cell lines and normal intestinal epithelial cells by qPCR and Western blotting. CCK-8 proliferation assays, transwell assays, wound healing assays, colony assays and flow cytometry were performed to clarified the effect of HRK on CRC cells. Western blotting and rescue experiments were used to determine the role of HRK in regulating PI3K/AKT/mTOR signaling pathway. Results:HRK expression was lower in CRC tissues and cell lines. Gain and loss of function experiments showed that HRK decreased proliferation, invasion and migration of CRC cells. Low expression of HRK inhibited CRC cell apoptosis as well as activated the PI3K/AKT/mTOR signaling pathway. In addition, rapamycin inhibits the activation of PI3K/AKT/mTOR signaling pathway and reverses HRK-induced alterations in cell biological functions. Conclusion:Our study demonstrates that HRK is lowly expressed in colorectal cancer tissues. And for the first time, HRK was shown to promote apoptosis and inhibit proliferation of colorectal cancer cells by inhibiting PI3K/AKT/mTOR signaling pathway. HRK represents a potential target for the treatment of CRC.

Phosphorescent iridium(III) complexes have been extensively investigated as cellular imaging reagents and sensors. The intracellular localization of the complexes is known to be closely related to their formal charge, molecular size, lipophilicity, and bioactive pendants. Herein, we reported four phosphorescent iridium(III) complexes with the diimine ligands being modified with ester or amide groups as imaging reagents for living cells. The complexes have the same positive charge and very similar molecular size and weight. The lipophilicity of the complexes is similar ranging from 1.45 to 2.14. Upon internalization into living HeLa cells, while complexes 2-4, like most other iridium(III) complexes, were localized in the cytoplasm, complex 1 unexpectedly stained the whole cells including nuclei. The nuclear uptake of complex 1 was not observed when the cells were pretreated with chlorpromazine or nocodazole, suggesting that clathrin and microtubules mediated the nuclear uptake of complex 1. Additionally, the nuclear uptake efficiency is related to the cell division cycle. The complex was mainly concentrated in the nucleus when the cells were in mitosis, and distributed in whole cells when the cells were in the interphases. Furthermore, complex 1 exhibited a longer luminescence lifetime in the nucleus than in the cytoplasm as revealed by photoluminescence lifetime imaging microscopy (PLIM). Incubation of the cells in the hypoxia environment elongated the lifetime of the cytoplasmic complex, but hardly affected the luminescence properties of the intranuclear complex.

Lung large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive malignancy with a dismal prognosis. This study was designed to depict patterns of distant organ metastatic and to analyze prognosis of LCNEC patients. We gathered data from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. We conducted the Kaplan-Meier method to calculate overall survival (OS) and compare different variables. Cox proportional hazards regression models in univariate and multivariate analyses were employed to further explore prognostic factors. A total of 1335 LCNEC patients were eventually selected from the SEER database, of which 348 patients (26.0%) had single organ metastasis and 197 patients (14.8%) had multiple metastases. Our study indicates that patients with single organ metastasis generally have a poor prognosis, with a median OS of 8 months for both lung and brain metastasis with 1-year survival rates of 33% and 29% respectively. Patients with multiple metastases exhibited the worst prognosis, with a median OS of only 4 months and a 1-year OS of 8%. Multivariate analysis revealed that age, T stage, N stage, chemotherapy and radiation in metastatic patients were independently associated with OS. In conclusion, LCNEC exhibits a high metastatic rate when diagnosed. The most common metastatic organ is the brain in single-site metastatic patients. Patients with single or multiple metastases exhibit a significantly worse prognosis than those with non-organ metastases. In the group of single organ metastases, patients with brain and lung metastases had a better prognosis than those with bone and liver metastases.

Probes featuring room-temperature phosphorescence (RTP) are promising tools for time-resolved imaging. It is worth noting that the time scale of time-resolved bioimaging generally ranges around the microsecond level, because of the short-lived emission. Herein, the first example of millisecond-range time-resolved bioimaging is illustrated, which is enabled through a kind of ultralong aqueous phosphorescence probes (i.e., cyclo-(Arg-Gly-AspD-Tyr-Cys)-conjugated zinc-doped silica nanospheres), with a RTP emission lasting for ≈5 s and a lifetime as long as 743.7 ms. We demonstrate that live cells and deep tumor tissue in mice can be specifically targeted through immune-phosphorescence imaging, with a high signal-to-background ratio (SBR) value of ≈69 for in vitro imaging, and ≈627 for in vivo imaging, respectively. We further show that, compared to that of fluorescence imaging, the SBR enhancement of millisecond-range time-resolved in vivo bioimaging is up to 105 times.