Enzymatic interlocking aptamer-micelles for enhanced cellular internalization and nucleus-targeted cancer phototherapy.

Multifunctional micelles that permit both diagnosis and treatment present enormous advantage and potential for precision medicine. However, the inherent complexities and structural instability of these systems often cause unsatisfactory targeting and therapeutic performances. Herein, by ingenious design of a 2,5-bis(2-thienyl)pyrrole (SNS) modifier to covalently link with AS1411 aptamer and lipid segment, a simple strategy is proposed for one-step enzymatic preparation of interlocked aptamer-micelle (IApM) under bio-friendly conditions. The interlocked poly(SNS) skeleton in IApM can not only stabilize the micelle structure but also enhance near-infrared (NIR) absorption ability, thus further enhancing cellular internalization and photothermal therapy. In addition, the multivalent AS1411 aptamers tethered in the hydrophilic shell can simultaneously increase the specific binding affinity of DNA micelles and induce nucleus-targeted accumulation for DNA damage-triggered apoptosis. This DNA micelle achieves "best of both worlds" with enhanced biostability for cellular internalization and improved NIR photothermal conversion efficiency for nucleus-targeted therapy, which provides a promising formulation strategy for precision cancer treatment.

Fixel-Based Analysis of White Matter Alterations in Facial Palsy.

Predicting individual prognosis is difficult despite various risk factor studies, due to the complex recovery involving peripheral nerve restoration and cerebral plasticity. This study uses fixel-based analysis (FBA) to better understand neural pathway alterations, hypothesizing that FBA can effectively link functional outcomes with diffusion metrics in the process of rehabilitation. The authors recruited 50 participants including 30 patients and 20 healthy controls into the study. All of them underwent assessment 3 months and 6 months after injury. Both whole-brain fixel-based analysis and tract of interest analysis were performed. The authors observed multiple regions including the superior corona radiata, posterior limb of the internal capsule, and cerebral peduncle displaying significant changes of FD (fiber density), FC (fiber-bundle cross-section), and FDC (fiber density and cross-section). Patients with unfavorable outcomes showed increased FD in the ipsilesional side and decreased FD in the contralesional side compared with patients with favorable outcomes. In addition, FD values of the contralesional side exhibited positive correlations with differences in FGS at 3 months and 6 months. Conversely, FD values in the ipsilesional side showed a negative correlation. Our findings suggest that FD metrics within the corticobulbar tract could serve as predictive biomarkers for symmetry outcomes. Thus, FBA holds promise for early estimation of behavioral outcomes in facial palsy, guiding more targeted interventions.

JARID2 activation by NFYA promotes stemness of triple-negative breast cancer cells through the PI3K/AKT pathway.

BACKGROUND: This study aimed to investigate the role of Jumonji AT Rich Interacting Domain 2 (JARID2) in regulating triple-negative breast cancer (TNBC) stemness and its mechanism. RESEARCH DESIGN AND METHODS: Bioinformatics analysis examined JARID2 expression, prognosis, and transcription factors. Quantitative polymerase chain reaction, western blot, and immunohistochemistry detected expression. Dual luciferase reporter gene and chromatin immunoprecipitation assays verified binding. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay detected viability and proliferation. Sphere formation assay detected the sphere formation efficiency. Flow cytometry detected CD44+/CD24- -marked stem cells. A xenograft tumor model verified the effect of JARID2 in vivo. RESULTS: JARID2 and nuclear transcription factor Y subunit α (NFYA) were upregulated in TNBC tissues and positively correlated. Knockdown of JARID2 or NFYA inhibited cell stemness by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. Enforced JARID2 expression rescued the suppressive effect of NFYA knockdown on the PI3K/AKT signaling pathway and cell stemness. Knockdown of JARID2 inhibited tumor growth and cell stemness in mice but was alleviated by concurrent overexpression of NFYA. CONCLUSIONS: NFYA promotes TNBC cell stemness by upregulating JARID2 expression and regulating the PI3K/AKT signaling pathway, suggesting JARID2 as a potential target for innovating drugs that target TNBC stem cells.

Ras promotes germline stem cell division in Drosophila ovaries.

The Ras family genes are proto-oncogenes that are highly conserved from Drosophila to humans. In Drosophila, RasV12 is a constitutively activated form of the Ras oncoprotein, and its function in cell-cycle progression is context dependent. However, how it influences the cell cycle of female germline stem cells (GSCs) still remains unknown. Using both wild-type GSCs and bam mutant GSC-like cells as model systems, here we determined that RasV12 overexpression promotes GSC division, not growth, opposite to that in somatic wing disc cells. Ras performs this function through activating the mitogen-activated protein kinase (MAPK) signaling. This signaling is activated specifically in the M phase of mitotic germ cells, including both wild-type GSCs and bam mutant GSC-like cells. Furthermore, RasV12 overexpression triggers polyploid nurse cells to die through inducing mitotic stress. Given the similarities between Drosophila and mammalian GSCs, we propose that the Ras/MAPK signaling also promotes mammalian GSC division.

Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability.

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.

Genetic circuitry controlling Drosophila female germline overgrowth.

Germ cells mutant for bam or bgcn are locked in a germline stem cell (GSC)-like state, leading to tumor-like overgrowth in Drosophila ovaries. Our previous studies have demonstrated that germline overgrowth in bam mutants can be suppressed by defects in the miRNA pathway but enhanced by a null mutation in hippo. However, the genetic epistasis between the miRNA and Hippo pathways still remains unknown. Here, we determined that the miRNA pathway acts downstream of the Hippo pathway in regulating this process. Germ cells mutant for bam or bgcn and defective in both pathways divide very slowly, phenocopying those defective only in the miRNA pathway. In addition, we found that Yki, a key oncoprotein in the Hippo pathway, promotes the growth of both wild-type germ cells and bam mutant GSC-like cells. Like wild-type GSCs, bam mutant GSC-like cells predominantly stay in the G2 phase. Remarkably, many of those defective in the miRNA pathway are arrested before entering this phase. Furthermore, our studies identified bantam as a critical miRNA promoting germline overgrowth in bam or bgcn mutants. Taken together, these findings establish a genetic circuitry controlling Drosophila female germline overgrowth.

Cell-drug conjugates.

By combining living cells with therapeutics, cell-drug conjugates can potentiate the functions of both components, particularly for applications in drug delivery and therapy. The conjugates can be designed to persist in the bloodstream, undergo chemotaxis, evade surveillance by the immune system, proliferate, or maintain or transform their cellular phenotypes. In this Review, we discuss strategies for the design of cell-drug conjugates with specific functions, the techniques for their preparation, and their applications in the treatment of cancers, autoimmune diseases and other pathologies. We also discuss the translational challenges and opportunities of this class of drug-delivery systems and therapeutics.

Contrast-enhanced ultrasound (CEUS) characteristics of atypical-enhanced papillary thyroid carcinoma (PTC).

OBJECTIVE: To investigate the diagnostic value of CEUS in atypical-enhanced PTC. METHODS: The clinical data, qualitative and quantitative parameters of CEUS in 177 Iso/hyper-enhanced thyroid nodules with definite pathological results were retrospectively analyzed in the Lanzhou University Second Hospital from June 2019 to January 2021. And the clinical value of CEUS in the diagnosis of atypical-enhanced PTC was assessed using univariate and multivariate analysis. RESULTS: Among the 177 thyroid nodules, 59 were benign and 118 were PTC. There were significant differences in age, enhancement border, ring enhancement, speed of wash in, speed of wash out, enhancement pattern, capsule interruption, time to peak, time to wash out, RT, TPH, and TTP (P < 0.05). Multivariate analysis showed unclear enhancement border and concentric enhancement were independent risk factors for the diagnosis of atypical-enhanced PTC by CEUS. The sensitivity, specificity, PPV, NPV, and accuracy of the model in diagnosing atypical-enhanced PTC were 88.1%, 71.2%, 86.0%, 75.0%, and 82.5%, respectively. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.910. CONCLUSION: The diagnosis of atypical-enhanced PTC can be better performed by enhancement characteristics and time intensity curve (TIC) of CEUS, which have a good clinical application value.

Protective effects of ginsenoside F2 on isoproterenol-induced myocardial infarction by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways.

BACKGROUND: Ginsenoside F2 (GF2) serves as the principal intestinal metabolite resulting from the oral intake of Panax ginseng and Panax quinquefolius, exhibiting antioxidative, hypolipidemic, antitumor, and anti-inflammatory properties. Nevertheless, its effect on myocardial infarction (MI) is still unknown. PURPOSE: The purpose of this study is to investigate the protective effect and the underlying mechanisms of GF2 against isoproterenol (ISO)-induced MI. METHODS: ISO-induced H9c2 cardiomyocytes and MI rat models were utilized as in vitro and in vivo models to evaluate the impact of anti-MI of GF2. The underlying mechanisms were investigated using a variety of methodologies, including electrocardiography, Western blot analysis, histopathological examination, immunofluorescence, immunohistochemistry, and ELISA techniques. RESULTS: In vivo experiments, our results indicated that GF2 significantly ameliorated ISO-induced electrocardiographic (ECG) abnormalities, myocardial fiber necrosis, rupture, fibrosis of myocardial tissues, and suppressed cardiac enzyme activities. Meanwhile, GF2 notably raised the activity of antioxidant enzymes like CAT, GSH, and SOD. Furthermore, it downregulated Keap1 expression level while upregulating NQO1, Nrf2, and HO-1 expression levels. Additionally, GF2 suppressed the expression of the cleaved caspase-3 and pro-apoptotic protein Bax while promoting the expression of anti-apoptotic proteins Bcl-2, p-PI3K, and p-Akt. TUNEL fluorescence results also demonstrated that GF2 effectively inhibited cardiomyocyte apoptosis. Furthermore, consistent with the results of animal experiments, GF2 considerably attenuated ROS generation, changed apoptosis and mitochondrial function, and reduced oxidative stress in ISO-induced H9c2 cardiomyocytes through activating Nrf2/HO-1 and PI3K/Akt signaling pathways. CONCLUSION: Taken together, GF2 ameliorated MI by preventing cardiocyte apoptosis, oxidative stress, and mitochondrial dysfunction via modulating the Nrf2/HO-1 and PI3K/Akt signaling pathways, showing potential as a treatment strategy for treating MI.

Bone Morphogenetic Protein 2 Enhances Porcine Beige Adipogenesis via AKT/mTOR and MAPK Signaling Pathways.

Bone morphogenetic protein 2 (BMP2) has been reported to regulate adipogenesis, but its role in porcine beige adipocyte formation remains unclear. Our data reveal that BMP2 is significantly induced at the early stages of porcine beige adipocyte differentiation. Additionally, supplementing rhBMP2 during the early stages, but not the late stages of differentiation, significantly enhances porcine SVF adipogenesis, thermogenesis, and proliferation. Furthermore, compared to the empty plasmid-transfected-SVFs, BMP2-overexpressed SVFs had the enhanced lipid accumulation and thermogenesis, while knockdown of BMP2 in SVFs exhibited the opposite effect. The RNA-seq of the above three types of cells revealed the enrichment of the annotation of thermogenesis, brown cell differentiation, etc. In addition, the analysis also highlights the significant enrichment of cell adhesion, the MAPK cascade, and PPARγ signaling. Mechanistically, BMP2 positively regulates the adipogenic and thermogenic capacities of porcine beige adipocytes by activating PPARγ expression through AKT/mTOR and MAPK signaling pathways.

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.

The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins. In recent years, toxins have been widely used as warheads for antibody‒drug conjugates (ADCs) due to their efficient killing activity against various cancer cells. Although ADCs confer certain targeting properties to the toxins, low drug loading capacity, possible immunogenicity, and other drawbacks also limit the potential application of ADCs. Recently, non-ADC delivery strategies for toxins have been extensively investigated. To further understand the application of toxins in anti-tumor, this paper provided an overview of prodrugs, nanodrug delivery systems, and biomimetic drug delivery systems. In addition, toxins and their combination strategies with other therapies were discussed. Finally, the prospect and challenge of toxins in cancer treatment were also summarized.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Rare NUP98::PRRX1 fusion transcript in a therapy-related acute myeloid leukemia associated with del(7q) following chemotherapy for diffuse large B-cell lymphoma.

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is increasingly recognized as a treatment complication in patients receiving chemotherapy, radiotherapy, or immunosuppressive agents for primary neoplasms. NUP98::PRRX1 fusion gene, caused by t(1;11)(q23;p15), is a rare recurrent cytogenetic alteration in leukemia, and only seven cases with NUP98::PRRX1 were reported so far. METHODS: A 53-year-old female patient was diagnosed with t-AML after 20 months of complete remission (CR) from diffuse large B-cell lymphoma (DLBCL). Conventional karyotype, fluorescence in situ hybridization (FISH), and DNA/RNA next-generation sequence (NGS) were used to detect genetic abnormalities. RESULTS: Abnormal karyotype of 46, XX, t(1;11)(q25;p15), del(7)(q22) was revealed. NUP98 gene rearrangement and del(7)(q22) were verified by FISH. Further, RNA NGS detected NUP98::PRRX1 fusion transcript, and DNA NGS detected KRAS gene mutation. The patient achieved CR after a combined chemotherapy regimen containing BCL-2 inhibitor and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but she died of leukemia recurrence 14 months later. CONCLUSIONS: Novel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance.

Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor.

The limited infiltration and persistence of chimeric antigen receptor (CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading, delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer.

Colorectal cancer (CRC) is a common malignancy involving multiple cellular components. The CRC tumor microenvironment (TME) has been characterized well at single-cell resolution. However, a spatial interaction map of the CRC TME is still elusive. Here, we integrate multiomics analyses and establish a spatial interaction map to improve the prognosis, prediction, and therapeutic development for CRC. We construct a CRC immune module (CCIM) that comprises FOLR2+ macrophages, exhausted CD8+ T cells, tolerant CD8+ T cells, exhausted CD4+ T cells, and regulatory T cells. Multiplex immunohistochemistry is performed to depict the CCIM. Based on this, we utilize advanced deep learning technology to establish a spatial interaction map and predict chemotherapy response. CCIM-Net is constructed, which demonstrates good predictive performance for chemotherapy response in both the training and testing cohorts. Lastly, targeting FOLR2+ macrophage therapeutics is used to disrupt the immunosuppressive CCIM and enhance the chemotherapy response in vivo.

1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study.

1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum ß2-microglobulin (7.24 g/L vs. 3.85 g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P = 0.002; PFS: 14 months vs. 38 months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.

A Novel Cu(II) Loaded Polypeptide SO2 Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies.

Sulfur dioxide (SO2)-based gas therapy and chemodynamic therapyare both reactive oxygen species (ROS)-mediated anticancer strategies, but there are few reports of their combined application. To this end, a novel graft-type copolymeric SO2 prodrug, PLG-g-mPEG-DNs, is designed and synthesized in this work. The amphiphilic polypeptides can self-assemble into nanoparticles (NPs) and encapsulated Cu(II) ions by metal-carboxyl coordination. In vitro release results showed that the obtained NPs-Cu can respond to the acidic pH and high glutathione levels typical of a tumor microenvironment to release Cu(II) and SO2 simultaneously. Both a Cu(II)-triggered Fenton-like reaction and the SO2 gas would promote ROS production and upregulate the oxidative stress in tumor cells, leading to an enhanced killing effect towards 4T1 cancer cells compared to either Cu(II) or the NPs alone. Furthermore, the in vitro hemolysis of NPs-Cu is less than 1.0% at a high concentration of 8 mg/mL, indicating good blood compatibility and the potential for in vivo tumor inhibition application.

A proteomic study on gastric impairment in rats caused by microcystin-LR.

Microcystins (MCs) are the most common cyanobacterial toxins. Epidemiological investigation showed that exposure to MCs can cause gastro-intestinal symptoms, gastroenteritis and gastric cancer. MCs can also accumulate in and cause histopathological damage to stomach. However, the exact mechanisms by which MCs cause gastric injury were unclear. In this study, Wistar rats were administrated 50, 75 or 100 µg microcystin-LR (MC-LR)/kg, body mass (bm) via tail vein, and histopathology, response of anti-oxidant system and the proteome of gastric tissues at 24 h after exposure were studied. Bleeding of fore-stomach and gastric corpus, inflammation and necrosis in gastric corpus and exfoliation of mucosal epithelial cells in gastric antrum were observed following acute MC-LR exposure. Compared with controls, activities of superoxide dismutase (SOD) were significantly greater in gastric tissues of exposed rats, while activities of catalase (CAT) were less in rats administrated 50 µg MC-LR/kg, bm, and concentrations of glutathione (GSH) and malondialdehyde (MDA) were greater in rats administrated 75 or 100 µg MC-LR/kg, bm. These results indicated that MC-LR could disrupt the anti-oxidant system and cause oxidative stress. The proteomic results revealed that MC-LR could affect expressions of proteins related to cytoskeleton, immune system, gastric functions, and some signaling pathways, including platelet activation, complement and coagulation cascades, and ferroptosis. Quantitative real-time PCR (qRT-PCR) analysis showed that transcriptions of genes for ferroptosis and gastric function were altered, which confirmed results of proteomics. Overall, this study illustrated that MC-LR could induce gastric dysfunction, and ferroptosis might be involved in MC-LR-induced gastric injury. This study provided novel insights into mechanisms of digestive diseases induced by MCs.

Anti-cancer targets and molecular mechanisms of formononetin in treating osteosarcoma based on network pharmacology.

Osteosarcoma (OS) is a multifactorial bone malignancy that accounts for most cancers in children and adolescents. Formononetin has been proven to exhibit various pharmacological effects including anti-tumor, anti-obesity, anti-inflammation, and neuroprotective effects. Few studies have examined the pharmacological activities of formononetin in OS treatment, but the mechanism has not yet been completely elucidated. Network pharmacology is a new method based on the theory of system biology for analyzing the network of biological systems and selecting specific signal nodes for multi-target drug molecular design. Here, we used network pharmacology to explore the possible mechanism of formononetin in OS treatment. Human OS cell line MG63 was processed with four concentrations (0, 2, 5, 8 µg/mL) of formononetin. Subsequently, an MTT assay was performed to test cell proliferation and a scratch test was used to evaluate the migration ability of cancer cells. Caspase-3, p53, p21, and bcl-2 expression levels incubated with different concentrations of formononetin in MG63 cells were determined using Western blotting. After treated with formononetin for 48 h, MG63 cells exhibited marked apoptosis. The results revealed that certain concentrations of formononetin significantly exerted inhibitory effects on MG63 cell proliferation. Furthermore, formononetin decreased the bcl-2 level in MG63 cells but increased caspase-3, p21, and p53 levels in a concentration-dependent manner. Additionally, formononetin suppressed the expression of SATB2. Therefore, formononetin could dose-dependently inhibit MG63 cell proliferation and induce apparent cell apoptosis, providing a candidate treatment for OS, whereas SATB2 could be a potential prognostic biomarker for screening OS and therapeutic target of formononetin.

Pre-activated nanoparticles with persistent luminescence for deep tumor photodynamic therapy in gallbladder cancer.

Phototherapy of deep tumors still suffers from many obstacles, such as limited near-infrared (NIR) tissue penetration depth and low accumulation efficiency within the target sites. Herein, stimuli-sensitive tumor-targeted photodynamic nanoparticles (STPNs) with persistent luminescence for the treatment of deep tumors are reported. Purpurin 18 (Pu18), a porphyrin derivative, is utilized as a photosensitizer to produce persistent luminescence in STPNs, while lanthanide-doped upconversion nanoparticles (UCNPs) exhibit bioimaging properties and possess high photostability that can enhance photosensitizer efficacy. STPNs are initially stimulated by NIR irradiation before intravenous administration and accumulate at the tumor site to enter the cells through the HER2 receptor. Due to Pu18 afterglow luminescence properties, STPNs can continuously generate ROS to inhibit NFκB nuclear translocation, leading to tumor cell apoptosis. Moreover, STPNs can be used for diagnostic purposes through MRI and intraoperative NIR navigation. STPNs exceptional antitumor properties combined the advantages of UCNPs and persistent luminescence, representing a promising phototherapeutic strategy for deep tumors.