Lipidomics reveals new lipid-based lung adenocarcinoma early diagnosis model.

Lung adenocarcinoma (LUAD) continues to pose a significant mortality risk with a lack of dependable biomarkers for early noninvasive cancer detection. Here, we find that aberrant lipid metabolism is significantly enriched in lung cancer cells. Further, we identified four signature lipids highly associated with LUAD and developed a lipid signature-based scoring model (LSRscore). Evaluation of LSRscore in a discovery cohort reveals a robust predictive capability for LUAD (AUC: 0.972), a result further validated in an independent cohort (AUC: 0.92). We highlight one lipid signature biomarker, PE(18:0/18:1), consistently exhibiting altered levels both in cancer tissue and in plasma of LUAD patients, demonstrating significant predictive power for early-stage LUAD. Transcriptome analysis reveals an association between increased PE(18:0/18:1) levels and dysregulated glycerophospholipid metabolism, which consistently displays strong prognostic value across two LUAD cohorts. The combined utility of LSRscore and PE(18:0/18:1) holds promise for early-stage diagnosis and prognosis of LUAD.

Immune cell-derived exosomes as promising tools for cancer therapy.

Exosomes are nanoscale vesicles with a size of 30-150 nm secreted by living cells. They are vital players in cellular communication as they can transport proteins, nucleic acids, lipids, and etc. Immune cell-derived exosomes (imEXOs) have great potential for tumor therapy because they have many of the same functions as their parent cells. Especially, imEXOs display unique constitutive characteristics that are directly involved in tumor therapy. Herein, we begin by the biogenesis, preparation, characterization and cargo loading strategies of imEXOs. Next, we focus on therapeutic potentials of imEXOs from different kinds of immune cells against cancer from preclinical and clinical studies. Finally, we discuss advantages of engineered imEXOs and potential risks of imEXOs in cancer treatment. The advantages of engineered imEXOs are highlighted, including selective killing effect, effective tumor targeting, effective lymph node targeting, immune activation and regulation, and good biosafety.

A CaCO3-based nanoplatform with sonodynamic and tumor microenvironment activated for combined in vitro cancer therapy.

INTRODUCTION: Sonodynamic therapy (SDT) has potential clinical applications for cancer therapy, and is yet restricted by complex tumor microenvironmental (TME) factors. Thus, the research problem of TME modulation as well as efficient tumor treatment still needs to be clarified. METHOD: In this study, a calcium carbonate (CaCO3) nanoplatform was designed for ultrasound (US) and TME response-triggered, which encapsulated Ag2S and loaded with l-Arg, and further wrapped with RBC/Platelet membrane, named as QD@Ca/ML-Arg. RESULTS: Non-invasive US-triggered SDT by Ag2S and acidic environment-responsive drug release were achieved. In vitro experiments validated the efficacy of SDT, Ca-ion interference and nitric oxide (NO) gas therapy as combined therapy for cancer treatment. By means of RNA sequencing, the cancer therapeutic mechanism of SDT in redox-related pathways was elucidated. The immunosuppressive TME was simulated with a M2-macrophage/cancer cell co-culture system to confirm the immune activating effect of immunogenic cell death (ICD). CONCLUSION: Accordingly, the potential of QD@Ca/ML-Arg-was demonstrated for in vitro TME modulation, cancer therapeutic efficacy and clinical translation.

Protocol for designing and preparing gallium particles using cell membrane encapsulation for applications in melanoma cryoablation therapy.

Liquid metals are increasingly applied in drug delivery, in vivo imaging, and biosensing. Herein, we describe a surface modification strategy, where cell membrane is introduced to encapsulate gallium (Ga) particles. We detail preparation steps of Ga microparticles by sonication, followed by Ga microparticles coating with purified tumor cell membranes and morphological assessment using TEM and cryo-TEM. We further describe cell uptake and establishment of tumor-bearing mouse models and steps to assess in vitro cytotoxicity and in vivo antitumor cryotherapy. For complete details on the use and execution of this protocol, please refer to Wang et al. (2022).

Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner.

BTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubrutinib, however, Acalabrutinib cytotoxicity was extremely weak. RNA-seq, followed by KEGG analysis and quantitative RT-PCR validation, was conducted to identify the differential apoptotic target genes of BTKis, leading to their distinct cytotoxic effects on endothelial cells, which showed that Ibrutinib and Zanubrutinib dramatically modulated the expression of critical apoptotic genes, GADD45B, FOS, and BCL2A1, among which FOS and GADD45B were upregulated more significantly by Ibrutinib than Zanubrutinib, however, Acalabrutinib downregulated BCL2A1 moderately and was not able to modulate the expression of FOS and GADD45B. Next, we performed in vitro angiogenesis assays and found that Ibrutinib was more able to induce endothelial dysfunction than Zanubrutinib via stimulating more BMP4 expression, however, Acalabrutinib had no such effect. Especially, the capacity of Ibrutinib to induce endothelial dysfunction can be antagonized by targeting BMP4. Accordingly, Ibrutinib, as an angiogenesis inhibitor, inhibited ovarian and breast cancer progression in vivo. Collectively, our findings addressed a novel molecular basis underlying Ibrutinib-induced endothelial cell dysfunction and suggested the potential application of Ibrutinib to treat angiogenesis-dependent cancers.

Targeted Therapy of Lung Adenocarcinoma by the Nanoplatform Based on Milk Exosomes Loaded with Paclitaxel.

Lung cancer is the most common cancer throughout the world. Currently, most lung cancer therapies are still limited by serious side effects caused. This paper reports a biocompatible drug delivery system that utilizes milk-derived exosomes to deliver paclitaxel to treat lung adenocarcinoma. First, milk-derived exosomes were modified with integrin αVß3, αVß5-binding peptide iRGD so that they could successfully target lung adenocarcinoma cells. Then, iRGD modified exosomes were loaded with paclitaxel (PAC) via electroporation and used for tumor therapy. These modified exosomes proved effective in killing lung adenocarcinoma cells, and the exosome-based nanoplatform showed no obvious toxicity to normal cells. Further more, the exosome-based nanoplatform could effectively penetrate the interior of the 3D tumor sphere, reaching more tumor cells and demonstrating that it is a promising tool for lung adenocarcinoma therapy.

Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy.

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

An amphiphilic dendrimer as a light-activable immunological adjuvant for in situ cancer vaccination.

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.

Rapid and efficient isolation and detection of extracellular vesicles from plasma for lung cancer diagnosis.

Extracellular vesicles (EVs) are cell-derived nanoscale vesicles that provide promising biomarkers for the non-invasive diagnosis of cancer because they carry important cancer-related DNA, RNA and protein biomarkers. However, the clinical application of EVs is limited by tedious and non-standardized isolation methods that require bulky instrumentation. Here, we propose an easy-to-operate, simple dielectrophoretic (DEP) method for EV isolation with higher recovery efficiency (>83%) and higher purity than ultracentrifugation (UC). The DEP chip reduces the isolation procedure from 8 h to 30 min. To facilitate subsequent analysis, our DEP chip achieved integration of EV isolation and in situ lysis of EVs for the first time. Our chip also achieved on-chip siRNA delivery to EVs isolated by DEP. We found that EVs isolated from the plasma of lung cancer patients contained higher levels of miR-21, miR-191 and miR-192 compared to those from healthy people. With on-chip detection, EGFR in EVs could distinguish lung cancer patients from healthy people. Overall, this study provides an efficient and practical approach to the isolation and detection of EVs, which could be used for the early diagnosis of lung cancer.

Isolation and Visible Detection of Tumor-Derived Exosomes from Plasma.

Exosomes are nanosized extracellular vesicles (ranging from 30 to 120 nm) released from many cells that provide promising biomarkers for the noninvasive diagnosis of cancer. However, traditional exosome-isolation methods are tedious, nonstandardized, and require bulky instrumentation, thus limiting its clinical applications. In this paper, an anion-exchange (AE)-based isolation method was first proposed to isolate exosomes directly from plasma and cell-culture medium with AE magnetic beads within 30 min. Exosomes isolated with AE magnetic beads had higher recovery efficiency (>90%) and less protein impurities than those isolated by ultracentrifugation (UC). Prostate-cancer (PCa) exosomes in plasma were detected in a visual, label-free, and quantitative manner with aptamer-capped Fe3O4 nanoparticles for the first time. The linear range of PCa exosomes was estimated from 0.4 × 108 to 6.0 × 108 particles/mL with a detection limit of 3.58 × 106 particles/mL. The present study provides an efficient and practical approach for the rapid isolation and visible detection of exosomes, which is promising for the early diagnosis of PCa.

Sensitive and rapid detection of pathogenic bacteria from urine samples using multiplex recombinase polymerase amplification.

Bacterial infections may cause severe diseases such as tuberculosis, sepsis, nephritis and cystitis. The rapid and sensitive detection of bacteria is a prerequisite for the treatment of these diseases. The current gold standard for bacterial identification is bacteriological culture. However, culture-based identification takes 3-7 days, which is time-consuming and laborious. In this study, bacteria in urine samples were enriched using a portable filter-based pipette. Then, a centrifugal chip was constructed to detect multiple pathogenic bacteria from urine samples by integrating the DNA extraction, multiplex recombinase polymerase amplification (RPA) and fluorescent detection together. This eliminated the time-consuming cultivation step, and thus accelerated the diagnosis of the urinary tract infections (UTIs). The five major pathogenic bacteria in UTIs were detected in this study, which are Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhimurium. Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus were successfully detected with limits of detection of 100 CFU mL-1 from urine samples within 40 min. Salmonella typhimurium was successfully detected with a limit of detection of 1000 CFU mL-1 from urine samples. The chip-based bacteria detection proposed in this study is a promising tool for sensitive, accurate, and multiplex identification of bacteria in clinical urine samples of UTIs and bacteriuria.