Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies.

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an "and" logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.

Sensitive and Low-Noise Perovskite Nanocrystal-Organic Bulk Heterostructure X-ray Detectors Enabled by Sodium Bromide-Assisted In Situ Reparation.

Perovskite nanocrystals (PNCs) offer unique advantages in large-area and thick-film deposition for X-ray detection applications due to the decoupling of the crystallization of perovskite from film formation, as well as their low-temperature and scalable deposition methods. However, the partial detachment of long-chain ligands in PNCs during the purification process would lead to the exposure of surface defects, making it challenging to ensure efficient charge carrier extraction and stable X-ray detection. In this study, we propose a beneficial strategy that involves the in situ reparation of these exposed defects with sodium bromide (NaBr) during the purification process to construct CsPbBr3 PNC-organic bulk heterostructure X-ray detectors. The NaBr-passivated PNCs exhibit stronger photoluminescence intensity and lower trap density in films compared to those of the control samples, confirming the effective passivation of halide vacancy defects. Furthermore, the NiOx hole transport layer with remarkable electron blocking capability is introduced to further suppress the dark current of the devices. Consequently, the optimal devices exhibit a large sensitivity of 4237 µC Gyair-1 cm-2 and a low dark current density of 10 nA cm-2, as well as improved operational stability, which allows for high-contrast and low-dose X-ray imaging applications.

Monolithic integration of perovskite heterojunction on TFT backplanes through vapor deposition for sensitive and stable x-ray imaging.

Metal halide perovskites exhibit substantial potential for advancing next-generation x-ray detection. However, fabricating high-performance pixelated imaging arrays remains challenging due to the substantial dark current density and stability issues associated with common organic-inorganic hybrid perovskites. Here, we develop a vapor deposition method to create the first all-inorganic perovskite heterojunction film. The heterojunction introduction effectively reduces the dark current density of detectors to about 0.8 nA·cm-2, satisfying thin-film transistor (TFT) integration standards, while also increases sensitivity to above 2.6 × 104 µC·Gyair-1·cm-2, thus giving rise to a record low detection limit of <1 nGyair·s-1 among all polycrystalline perovskite-based x-ray detectors. The devices also demonstrate remarkable stability across multifarious demanding working conditions. Last, through monolithic integration of the heterojunction film with a 64 × 64 pixelated TFT array, we have achieved high-resolution real-time x-ray imaging, which paves the way for the application of all-inorganic perovskite in low-dose flat-panel x-ray detection.

Advancements in the Research of GEF-H1: Biological Functions and Tumor Associations.

Guanine nucleotide exchange factor H1 (GEF-H1) is a unique protein modulated by the GDP/GTP exchange. As a regulator of the Rho-GTPase family, GEF-H1 can be activated through a microtubule-depended mechanism and phosphorylation regulation, enabling it to perform various pivotal biological functions across multiple cellular activities. These include the regulation of Rho-GTPase, cytoskeleton formation, cellular barrier, cell cycle, mitosis, cell differentiation, and vesicle trafficking. Recent studies have revealed its crucial effect on the tumor microenvironment (TME) components, promoting tumor initiation and progress. Consequently, an in-depth exploration of GEF-H1's biological roles and association with tumors holds promise for its potential as a valuable molecular target in tumor treatment.

Lattice-Gradient Perovskite KTaO3 Films for an Ultrastable and Low-Dose X-Ray Detector.

Conventional indirect X-ray detectors employ scintillating phosphors to convert X-ray photons into photodiode-detectable visible photons, leading to low conversion efficiencies, low spatial resolutions, and optical crosstalk. Consequently, X-ray detectors that directly convert photons into electric signals have long been desired for high-performance medical imaging and industrial inspection. Although emerging hybrid inorganic-organic halide perovskites, such as CH3 NH3 PbI3 and CH3 NH3 PbBr3 , exhibit high sensitivity, they have salient drawbacks including structural instability, ion motion, and the use of toxic Pb. Here, this work reports an ultrastable, low-dose X-ray detector comprising KTaO3 perovskite films epitaxially grown on a Nb-doped strontium titanate substrate using a low-cost solution method. The detector exhibits a stable photocurrent under high-dose irradiation, high-temperature (200 °C), and aqueous conditions. Moreover, the prototype KTaO3 -film-based detector exhibits a 150-fold higher sensitivity (3150 µC Gyair -1 cm-2 ) and 150-fold lower detection limit (<40 nGyair s-1 ) than those of commercial α-Se-based direct detectors. Systematic investigations reveal that the high stability of the detector originates from the strong covalent bonds within the KTaO3 film, whereas the low detection limit is due to a lattice-gradient-driven built-in electric field and the high insulating property of KTaO3 film. This study unveils a new path toward the fabrication of green, stable, and low-dose X-ray detectors using oxide perovskite films, which have significant application potential in medical imaging and security operations.

Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells.

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

Cellular specificity of lactate metabolism and a novel lactate-related gene pair index for frontline treatment in clear cell renal cell carcinoma.

Background: Although lactate metabolism-related genes (LMRGs) have attracted attention for their effects on cancer immunity, little is known about their function in clear cell renal cell carcinoma (ccRCC). The aim of this study was to examine the cellular specificity of lactate metabolism and how it affected the first-line treatment outcomes in ccRCC. Methods: GSE159115 was used to examine the features of lactate metabolism at the single-cell level. Utilizing the transcriptome, methylation profile, and genomic data from TCGA-KIRC, a multi-omics study of LMRG expression characteristics was performed. A prognostic index based on a gene-pair algorithm was created to assess how LMRGs affected patients' clinical outcomes. To simulate the relationship between the prognostic index and the frontline treatment, pRRophetic and Subclass Mapping were used. E-MTAB-1980, E-MTAB-3267, Checkmate, and Javelin-101 were used for external validation. Results: The variable expression of some LMRGs in ccRCC can be linked to variations in DNA copy number or promoter methylation levels. Lactate metabolism was active in tumor cells and vSMCs, and LDHA, MCT1, and MCT4 were substantially expressed in tumor cells, according to single-cell analysis. The high-risk patients would benefit from immune checkpoint blockade monotherapy (ICB) and ICB plus tyrosine kinase inhibitors (TKI) therapy, whereas the low-risk individuals responded to mTOR-targeted therapy. Conclusions: At the single-cell level, our investigation demonstrated the cellular specificity of lactate metabolism in ccRCC. We proposed that the lactate-related gene pair index might be utilized to identify frontline therapy responders in ccRCC patients as well as predict prognosis.

Coordination-driven FBXW7 DNAzyme-Fe nanoassembly enables a binary switch of breast cancer cell cycle checkpoint responses for enhanced ferroptosis-radiotherapy.

Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe2+-mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. STATEMENT OF SIGNIFICANCE: To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair, eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.

Crosstalk between autophagy and bladder transitional cell carcinoma by autophagy-related lncRNAs.

The aim of this study was to investigate the crosstalk between autophagy and bladder transitional cell carcinoma (TCC) by autophagy-related long noncoding RNAs (lncRNAs). A total of 400 TCC patients from The Cancer Genome Atlas were enrolled in this study. We identified the autophagy-related lncRNA expression profile of the TCC patients and then constructed a prognostic signature using the least absolute shrinkage and selection operation and Cox regression. Risk, survival, and independent prognostic analyses were carried out. Receiver operating characteristic curve, nomogram, and calibration curves were explored. Gene Set Enrichment Analysis was employed to verify the enhanced autophagy-related functions. Finally, we compared the signature with several other lncRNA-based signatures. A 9-autophagy-related lncRNA signature was established by least absolute shrinkage and selection operation-Cox regression that was significantly associated with overall survival in TCC. Among them, 8 of the 9 lncRNAs were protective factors while the remaining was a risk factor. The risk scores calculated by the signature showed significant prognostic value in survival analysis between the high- or low-risk groups. The 5-year survival rate for the high-risk group was 26.0% while the rate for the low-risk group was 56.0% (P < .05). Risk score was the only significant risk factor in the multivariate Cox regression survival analysis (P < .001). A nomogram connecting this signature with clinicopathologic characteristics was assembled. To assess the performance of the nomogram, a C-index (0.71) was calculated, which showed great convergence with an ideal model. The Gene Set Enrichment Analysis results demonstrated 2 major autophagy-related pathways were significantly enhanced in TCC. And this signature performed a similar predictive effect as other publications. The crosstalk between autophagy and TCC is significant, and this 9 autophagy-related lncRNA signature is a great predictor of TCC.

Clinical progress of anti-angiogenic targeted therapy and combination therapy for gastric cancer.

The incidence of gastric cancer is increasing year by year. Most gastric cancers are already in the advanced stage with poor prognosis when diagnosed, which means the current treatment is not satisfactory. Angiogenesis is an important link in the occurrence and development of tumors, and there are multiple anti-angiogenesis targeted therapies. To comprehensively evaluate the efficacy and safety of anti-angiogenic targeted drugs alone and in combination against gastric cancer, we systematically searched and sorted out relevant literature. In this review, we summarized the efficacy and safety of Ramucirumab, Bevacizumab, Apatinib, Fruquintinib, Sorafenib, Sunitinib, Pazopanib on gastric cancer when used alone or in combination based on prospective clinical trials reported in the literature, and sorted response biomarkers. We also summarized the challenges faced by anti-angiogenesis therapy for gastric cancer and available solutions. Finally, the characteristics of the current clinical research are summarized and suggestions and prospects are raised. This review will serve as a good reference for the clinical research of anti-angiogenic targeted drugs in the treatment of gastric cancer.

Structurally dynamic self-healable hydrogel cooperatively inhibits intestinal inflammation and promotes mucosal repair for enhanced ulcerative colitis treatment.

Hydrogels are a class of biocompatible materials with versatile functions that have been increasing explored for the localized treatment of ulcerative colitis (UC), but various mechanical stimuli may cause premature hydrogel breakage and detachment, impeding their further clinical translation. Here we report a multifunctional mechanically-resilient self-healing hydrogel for effective UC treatment, which is synthesized through the host-guest interaction between dopamine/ß-cyclodextrin-modified hyaluronic acid (HA-CD-DA) and amantadine-modified carboxymethyl chitosan (CMCS-AD). The excessive ß-CD cavities allow the incorporation of dexamethasone (DEX), while the porous hydrogel network potentiates the encapsulation of basic fibroblast growth factor (bFGF) and L-alanyl-l-glutamine (ALG). DA moieties in HA components allow firm adhesion of the hydrogel to the ulcerative lesions after in-situ implantation, while the reversible host-guest interaction between CD and AD could enhance the persistence of hydrogel. The hydrogel demonstrated favorable biocompatibility and could continuously release DEX to induce M1-to-M2 repolarization of mucosal macrophages through inhibiting the toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis. Furthermore, the co-delivered bFGF and ALG facilitates the regeneration of ulcerative mucosa and restore its barrier functions to ameliorate UC symptoms. The mechanically resilient hydrogel offers an integrative approach for UC therapy in the clinics.