Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. METHODS: From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. RESULTS: Compared with ctDNA-negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37-5.48; P = 0.003], while patients with positive post-ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08-72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival (RFS). Moreover, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index (0.78; 95% CI = 0.71-0.84) than the model without ctDNA (0.71; 95% CI = 0.64-0.79; P = 0.009). CONCLUSIONS: Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue-based and circulating tumor features could achieve better risk prediction.

Rational design of genotyping nanodevice for HPV subtype distinction.

There are more than 200 subtypes of human papillomavirus (HPV), and high-risk HPVs are a leading cause of cervical cancer. Identifying the genotypes of HPV is significant for clinical diagnosis and cancer control. Herein, we used programmable and modified DNA as the backbone to construct fluorescent genotyping nanodevice for HPV subtype distinction. In our strategy, the dye-labeled single-stranded recognize-DNA (R-DNA) was hybridized with Black Hole Quencher (BHQ) labeled single-stranded link-DNA (L-DNA) to form three functionalized DNA (RL-DNA). Through the extension of polycytosine (poly-C) in L-DNA, three RL-DNAs can be more firmly adsorbed on graphene oxide to construct reliable genotyping nanodevice. The genotyping nanodevice had low background noise since the dual energy transfer, including Förster resonance energy transfer (FRET) from dye to BHQ and the resonance energy transfer (RET) from dye to graphene oxide. Meanwhile, the programmability of DNA allows the proposed strategy to simultaneously and selectively distinguish several HPV subtypes in solution using DNA labeled with different dyes. To demonstrate clinical potential, we show multiplexed assay of HPV subtypes in cervical scrapes, and it has been successfully applied in HPV-DNA analysis in cervical scrapes samples. The genotyping nanodevice could be developed for simultaneous and multiplex analysis of several oligonucleotides in a homogeneous solution by adjusting the recognition sequence, demonstrating its potential application in the rapid screening of multiple biomarkers.

Simultaneous Response of Mitochondrial MicroRNAs to Identify Cell Apoptosis with Multiple Responsive Intelligent DNA Biocomputing Nanodevices.

Challenges remained in precisely real-time monitoring of apoptotic molecular events at the subcellular level. Herein, we developed a new type of intelligent DNA biocomputing nanodevices (iDBNs) that responded to mitochondrial microRNA-21 (miR-21) and microRNA-10b (miR-10b) simultaneously which were produced during cell apoptosis. By hybridizing two hairpins (H1 and H2) onto DNA nanospheres (DNSs) that had been previously modified with mitochondria-targeted triphenylphosphine (TPP) motifs, iDBNs were assembled in which two localized catalytic hairpins self-assembly (CHA) reactions occurred upon the co-stimulation of mitochondrial miR-21 and miR-10b to perform AND logic operations, outputting fluorescence resonance energy transfer (FRET) signals for sensitive intracellular imaging during cell apoptosis. Owing to the spatial confinement effects of DNSs, it was discovered that iDBNs had a high efficiency and speed of logic operations by high local concentrations of H1 and H2, making the simultaneous real-time responses of mitochondrial miR-21 and miR-10b reliable and sensitive during cell apoptosis. These results demonstrated that iDBNs were simultaneously responsive to multiple biomarkers, which greatly improved the detection accuracy to identify the cell apoptosis, demonstrating that iDBNs are highly effective and reliable for the diagnosis of major disease and screening of anticancer drugs.

Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis.

BACKGROUND: Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. METHODS: Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. RESULTS: In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. CONCLUSIONS: Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis.

[Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis]. / 利妥昔单抗治疗儿童及青少年成熟Bç»†èƒžéžéœå¥‡é‡‘æ·‹å·´ç˜¤ç–—æ•ˆåŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. METHODS: The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. RESULTS: The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). CONCLUSIONS: The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Dark-Field Imaging Monitoring of Adenosine Triphosphate in Live Cells by Au NBPs@ZIF-8 Nanoprobes.

Monitoring the fluctuation of adenosine triphosphate (ATP) level in living cells could promote the understanding of metabolic pathways and cell biology. Here, we proposed a highly sensitive, selective, and biocompatible nanoprobe with core-shell structure, namely Au NBPs@ZIF-8 composed by gold nanobipyramids (Au NBPs) and zeolitic imidazolate framework-8 (ZIF-8), for monitoring intracellular ATP level fluctuation in living cells. Because the coordination between ATP and Zn2+ (the metal node of ZIF-8) was much stronger than that between 2-methylimidazole and Zn2+, which caused the decomposition of the ZIF-8 shell and the exposure of Au NBPs in the presence of ATP, it led to the change of the localized surface plasmon resonance scattering properties of nanoprobes under dark-field microscopy. Tricolor (RGB) analysis showed that R/G value had a good linear relationship with the ATP concentrations in the range of 10 µM to 4 mM (R2 = 0.999) with a detection limit of 5.28 µM. This ATP sensing platform also exhibited excellent selectivity in complex intracellular interfering substances. Besides, we realized intracellular ATP real-time imaging in HeLa cells and observed the ATP level fluctuation under dark-field microscopy. The method mentioned here could be further applied for delivery of therapeutics for biomedical applications.

Genomic Analysis Uncovers the Prognostic and Immunogenetic Feature of Pyroptosis in Gastric Carcinoma: Indication for Immunotherapy.

Crosstalk between pyroptosis and tumor immune microenvironment (TIME) in cancer has yet to be elucidated. Herein, we aimed to explore the role of pyroptosis and its association with TIME in gastric cancer. Unsupervised clustering was performed to identify the pyroptosis-related clusters. Pyroptosis risk score was constructed using LASSO Cox regression. Clinicopathological and genetic data of pyroptosis clusters and pyroptosis risk scores were explored. Reproducibility of pyroptosis risk score in predicting response to immunotherapy and screening potential antitumor drugs was also investigated. Three pyroptosis clusters with distinct prognosis, immune cell fractions and signatures, were constructed. A low-pyroptosis risk score was characterized by increased activated T-cell subtype and M1 macrophage, decreased M2 macrophage, higher MSI status, and TMB. Meanwhile, low-score significantly correlated with PD-L1 expression, antigen presentation markers, and IFN-γ signature. The 5-year AUCs of PRS were 0.67, 0.62, 0.65, 0.67, and 0.67 in the TCGA, three external public and one real-world validation (SYSUCC) cohorts. Multivariable analyses further validated the prognostic performance of the pyroptosis risk scoring system, with HRs of 2.43, 1.83, 1.78, 2.35, and 2.67 (all p < 0.05) in the five cohorts. GSEA indicated significant enrichment of DNA damage repair pathways in the low-score group. Finally, the pyroptosis risk scoring system was demonstrated to be useful in predicting response to immunotherapy, and in screening potential antitumor drugs. Our study highlights the crucial role of interaction between pyroptosis and TIME in gastric cancer. The pyroptosis risk scoring system can be used independently to predict the survival of individuals and their response to immunotherapy.

Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma.

Background: We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma. Methods: Randomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model. Results: Seventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73. Conclusions: PFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ≤ 0.73 has the potential to predict a significant improvement in OS.

[Clinical features and prognosis of children with Burkitt's lymphoma: an analysis of 62 cases]. / 儿童伯基特淋巴瘤62例临床特征及预后分析.

OBJECTIVES: To study the clinical features and chemotherapy response of Burkitt's lymphoma (BL) in children and the influence of rituximab on the prognosis of children with BL. METHODS: A retrospective analysis was performed for the medical data of 62 children with BL, including clinical features, therapeutic efficacy, and prognostic factors. The Cox regression model was used to identify the factors associated with poor prognosis in children with BL. According to whether rituximab was used, the children with advanced (stage III/IV) BL were divided into two groups: chemotherapy plus rituximab and chemotherapy alone. The prognosis was compared between the two groups. RESULTS: For these 62 children, the median age of onset was 5 years (range 1-14 years), and there were 58 boys (94%) and 4 girls (6%). The primary site was abdominal cavity in 41 children (66%), and head and neck in 16 children (26%). There were 1 child with stage I BL (2%), 8 with stage II BL (13%), 33 with stage III BL (53%), and 20 with stage IV BL (32%). The median follow-up time was 29 months, with progression/recurrence observed in 15 children (24%), and the 3-year overall survival (OS) rate and event-free survival (EFS) rate were 82.8%±5.2% and 77.3%±5.8%, respectively. For the children with stage III/IV BL, there was a significant difference in the 3-year the OS rate between the chemotherapy plus rituximab group (16 children) and the chemotherapy alone group (30 children) (93.3%±6.4% vs 65.6%±9.9%, P=0.042), while there was no significant difference in the 3-year EFS rate between the two groups (86.2%±9.1% vs 61.8%±10.1%, P>0.05). The Cox regression analysis showed that central nervous system involvement, lactate dehydrogenase >1 000 U/L, and early incomplete remission were the factors associated with poor prognosis (P<0.05). CONCLUSIONS: Chemotherapy combined with rituximab can improve the prognosis of children with stage III/IV BL. Central nervous system involvement, elevated lactate dehydrogenase level, and early incomplete remission may indicate a poor prognosis in children with BL.

DNA Logic Nanodevices for the Sequential Imaging of Cancer Markers through Localized Catalytic Hairpin Assembly Reaction.

Monitoring tumor biomarkers is crucial for cancer diagnosis, progression monitoring, and treatment. However, identifying single or multiple biomarkers with the same spatial locations can cause false-positive feedback. Herein, we integrated the DNA tetrahedron (DT) structures with logic-responsive and signal amplifying capability to construct transmembrane DNA logic nanodevices (TDLNs) for the in situ sequential imaging of transmembrane glycoprotein mucin 1 (MUC1) and cytoplasmic microRNA-21 (miR-21) to cell identifications. The TDLNs were developed by encoding two metastable hairpin DNAs (namely, H1 and H2) in a DT scaffold, in which the triggering toeholds of H1 for miR-21 were sealed by the MUC1-specific aptamer (MUC1-apt). The TDLNs not only had the function of signal amplification owing to the localized catalytic hairpin assembly (CHA) reaction through spatial constraints effect of DT structures but also performed an AND logic operation to output a green Cy3 signal in MCF-7 cells, where MUC1 protein and miR-21 were simultaneously expressed. These results showed that the newly developed TDLNs have better molecular targeting and recognition ability so as to be easily identify cell types and diagnose cancer early.

Adjuvant Chemotherapy for Gastric Cancer Patients with Mismatch Repair Deficiency or Microsatellite Instability: Systematic Review and Meta-Analysis.

BACKGROUND: Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) status serves as a predictor of a poor response to adjuvant chemotherapy among stage 2 colon cancer patients. This study aimed to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). METHODS: Clinical studies comparing adjuvant chemotherapy and surgery alone in dMMR/MSI-H GCs through June 2021 were retrieved to assess the survival of patients managed with both treatments. Two approaches were used to pool the hazard ratio (HR) of survival: (1) if Kaplan-Meier curves and number of patients at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with its 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. RESULTS: Seven clinical studies were assessed. For dMMR/MSI-H versus mismatch repair-proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L) status, the estimated 5-year disease-free survival (DFS) rate was 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001) and the estimated 5-year OS rate was 60.5% versus 49.1% (HR, 0.71; 95% CI, 0.60-0.85; P < 0.001). The study-level data showed pooled HRs of 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.65 for OS (95% CI, 0.38-1.11; P = 0.114). For adjuvant chemotherapy versus observation of dMMR/MSI-H, the estimated 5-year DFS rate was 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171) and the estimated 5-year OS rate was 73.5% versus 59.7% (HR, 0.62; 95% CI, 0.46-0.83; P = 0.001). Significant survival differences also were observed at study level. CONCLUSIONS: The study findings confirm the benefit of adjuvant chemotherapy for dMMR/MSI-H GC patients.

DNA Logic Nanodevices for Real-Time Monitoring of ATP in Lysosomes.

DNA logic nanodevices have prospects in molecular recognitions but still face challenges in achieving DNA computation-controlled regulation in specific compartments of living cells. By incorporating the i-motif sequence and ATP aptamers into a Y-shaped DNA (Y-DNA) structure, and applying gold nanoparticles (AuNPs) as the transporting carrier, herein we present a new type of DNA logic nanodevices to monitor the ATP levels in lysosomes of living cells. Triple energy transfers including dual fluorescent resonance energy transfers (FRETs) and a nanometal surface energy transfer (NSET) occurred in the DNA logic nanodevices. It was identified that the proposed nanodevices perform an AND logic operation to output FRET signals only when an endogenous proton and ATP simultaneously exist in the cellular microenvironment. Owing to the use of the i-motif sequence, the nanodevices have lysosome-recognizing capacity without causing alkalization of the acidic organelle, making DNA computation-controlled regulation at the level of cellular organelles achievable. These DNA logic nanodevices show high application prospects in lysosome-related cellular function and disease treatment.

Transformable Helical Self-Assembly for Cancerous Golgi Apparatus Disruption.

Golgi apparatus is a major subcellular organelle responsible for drug resistance. Golgi apparatus-targeted nanomechanical disruption provides an attractive approach for killing cancer cells by multimodal mechanism and avoiding drug resistance. Inspired by the poisonous twisted fibrils in Alzheimer's brain tissue and enhanced rigidity of helical structure in nature, we designed transformable peptide C6RVRRF4KY that can self-assemble into nontoxic nanoparticles in aqueous medium but transformed into left-handed helical fibrils (L-HFs) after targeting and furin cleavage in the Golgi apparatus of cancer cells. The L-HFs can mechanically disrupt the Golgi apparatus membrane, resulting in inhibition of cytokine secretion, collapse of the cellular structure, and eventually death of cancer cells. Repeated stimulation of the cancers by the precursors causes no acquired drug resistance, showing that mechanical disruption of subcellular organelle is an excellent strategy for cancer therapy without drug resistance. This nanomechanical disruption concept should also be applicable to multidrug-resistant bacteria and viruses.

Aggregation-Enhanced Energy Transfer for Mitochondria-Targeted ATP Ratiometric Imaging in Living Cells.

Förster resonance energy transfer (FRET) from fluorescent nanoparticles to fluorescent dyes is an attractive approach for bioanalysis in living cells. However, the luminescence of the nanoparticle donor/acceptor has not been effectively used to produce highly efficient FRET because the distance between the energy donor and energy acceptor is often larger than the effective FRET radius (about 10 nm) and the uncontrolled rotational and translational diffusion of luminophores. Here, we develop an aggregation-enhanced energy transfer strategy that can overcome the impedance for effective energy transfer. The functional nanoprobes, named TPP-CDs-FITC, are carbon dots (CDs) functionalized with triphenylphosphine (TPP) and ∼117 fluorescein 5-isothiocyanate (FITC) on the surface. In dispersed solution, the 3.8 nm TPP-CDs-FITC show weak FRET efficiency (15.4%). After TPP-instructed mitochondrial targeting, enhanced FRET efficiency (53.2%) is induced due to the aggregation of TPP-CDs-FITC selectively triggered by adenosine triphosphate (ATP) in the mitochondria. The enhanced FRET efficiency can be attributed to the joint effect of the augment of numbers of FITC acceptors within 10 nm from dispersed 117 to aggregated 5499 and the restricted rotational and translational motions of TPP-CDs donors and FITC acceptors. Ultimately, we successfully observe the fluctuations of ATP levels in the mitochondria using the aggregation-enhanced energy transfer strategy of the TPP-CDs-FITC nanodevice.