Poor tumor accumulation, rapid clearance from blood circulation, and high risk of invasive and metastasis are the major barriers that encumber the conventional nanodrug-based tumor therapy. In this work, macrophage membrane (M)-camouflaged quercetin (QE)-loaded hollow bismuth selenide nanoparticles (abbreviated as M@BS-QE NPs) are fabricated for combination therapy of breast cancer. The resulting M@BS-QE NPs are comprehensively characterized, possessing prolonged circulation life, as well as accelerated and enhanced tumoritropic accumulation, compared with those of bare BS NPs because of the immune evading capacity, C-C chemokine ligand 2 (CCL2)-mediated recruitment properties, and active targeting ability. The subsequent QE release under near-infrared (NIR) laser irradiation can selectively sensitize cancer cells to photothermal therapy (PTT) by depleting heat shock protein 70 (HSP70, one malignancy-specific-overexpressed thermoresistance-related chaperone) to realize such a cascaded synergistic effect. At the same time, M@BS-QE NPs down-regulated p-Akt and matrix metalloproteinase-9 (MMP-9, which degrades the extracellular matrix to promote invasion and metastasis of tumors) signal axis to suppress breast cancer lung metastasis. Thus, our results provide a biomimetic strategy, using the characteristics of breast cancer and biological properties of macrophages, that hold great promise to enhance the therapeutic efficacy and improve the accuracy of treatment with minimal side effects on both primary and lung metastasis of breast cancer.

Extracellular vesicles (EV) have attracted increasing attention as tumour biomarkers due to their unique biological property. However, conventional methods for EV analysis are mainly based on bulk measurements, which masks the EV‐to‐EV heterogeneity in tumour diagnosis and classification. Herein, a localized fluorescent imaging method (termed Digital Profiling of Proteins on Individual EV, DPPIE) was developed for analysis of multiple proteins on individual EV. In this assay, an anti‐CD9 antibody engineered biochip was used to capture EV from clinical plasma sample. Then the captured EV was specifically recognized by multiple DNA aptamers (CD63/EpCAM/MUC1), followed by rolling circle amplification to generate localized fluorescent signals. By‐analyzing the heterogeneity of individual EV, we found that the high‐dimensional data collected from each individual EV would provide more precise information than bulk measurement (ELISA) and the percent of CD63/EpCAM/MUC1‐triple‐positive EV in breast cancer patients was significantly higher than that of healthy donors, and this method can achieve an overall accuracy of 91%. Moreover, using DPPIE, we are able to distinguish the EV between lung adenocarcinoma and lung squamous carcinoma patients. This individual EV heterogeneity analysis strategy provides a new way for digging more information on EV to achieve multi‐cancer diagnosis and classification.

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Background: Cancer-associated fibroblasts (CAFs), as the activated stroma cells, contribute to tumor progression via the release of cytokines, growth factors, and hormones. However, neither the factors produced by CAFs nor the molecular mechanisms were illuminated very well in gastric cancer (GC).Methods: Immunohistochemical staining of alpha-smooth muscle actin (α-SMA) was applied to examine the number of CAFs in GC samples from 227 patients. ELISA and qRT-PCR were performed to detect the expression of interleukin 17a (IL-17a). The migration and invasion of GC cells were determined by the Transwell assay. The expressions of JAK2, STAT3, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by western blotting. IL-17a was blocked with a polyclonal antibody, and JAK2/STAT3 signaling pathway was blocked by a specific inhibitor AG490.Results: High CAFs in GC tissues were positively correlated with advanced TNM stage and perineural invasion. Furthermore, GC patients with high CAFs in tumor tissues had an obvious worse disease-free survival (DFS) and disease-special survival (DSS). Multivariate analysis showed that high CAFs in GC tissues were an independent risk factor for DFS and DSS. CAFs expressed IL-17a significantly after GC cell co-culture. CAFs markedly enhanced the migration and invasion abilities of AGS and SGC-7901 cells.Moreover, CAFs co-culture resulted in increased levels of MMP2/9, reduced expressions of TIMP1/2, and activation of the JAK2/STAT3 signaling pathway in the GC cells. IL-17a neutralizing antibody or JAK2 inhibitor AG490 can significantly inhibit the effects of CAFs on the migration, invasion, MMP2/9, TIMP1/2, and JAK2/STAT3 pathways of GC cells.Conclusions: CAFs correlated with unfavorable clinical features and poor prognosis of GC patients. CAFs secreted IL-17a, which promoted the migration and invasion of GC cells through activating JAK2/STAT3 signaling. These results may identify IL-17a as a promising prognostic marker and therapeutic target of GC.

Exosomal miRNAs play a critical role in cancer biology and could be potential biomarkers for cancer diagnosis. However, due to the low abundance of miRNAs in the exosomes, recognizing and detecting disease-associated exosomal miRNAs in an easy-to-operate way remain a challenge. Herein, we used a liposome-mediated membrane fusion strategy (MFS) to transfect CRISPR/Cas13a into exosomes, termed MFS-CRISPR, directly measuring exosomal miRNAs in plasma. Using the MFS-CRISPR platform for detection of the exosomal miR-21, we achieve a linear range spanning four orders of magnitude (104–108 particles/mL) and the method is able to detect the exosomal miR-21 in as low as 1.2 × 103 particles/mL. The liposome-mediated MFS could confine fluorescent signals in fused vesicles, which can be used for exosome heterogeneity analysis. Moreover, MFS-CRISPR assay was evaluated by measuring clinical samples, and the difference of miR-21 expression of breast cancer patients and healthy donors was significant. Because of high sensitivity and simplicity, the proposed method could have promising clinical potential for cancer diagnosis and treatment monitoring.

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Tumor-derived exosomes are emerging noninvasive biomarker reservoirs that reflect biological information from their parental cells, especially specific markers, including proteins, DNA fragments and RNAs. Recently, analytical methods of tumor-derived exosomes have been increasing growth. However, developing a convenient signal amplification technique to improve the sensitivity of exosomes detection still remains a challenge. Herein, an ultrasensitive and specific exosomes diagnostic biochip is constructed and further applied to circulating tumor exosomes detection in serum. Using an exosomes diagnostic biochip, signal amplification is achieved by combining the advantages of quantum dots with the biomimetic periodic nanostructure of photonic crystals. Glypican-1 (GPC1), a membrane-anchored protein that is overexpressed in exosomes from pancreatic cancer, is detected using nanosized molecular beacons with high luminescence efficiency; then the signal is amplified through photonic crystals. Moreover, the method allows the quantitative analysis of various disease-specific surface proteins on exosomes. We believe that this exosomes diagnostic biochip is likely to have potential as an effective bioassay, which may be helpful for quantification of disease-specific exosomes in clinical use.