Exosomes are small membrane vesicles secreted by most cell types, and appear ubiquitously in cell culture supernatants and body fluids. Increasing evidence supports that exosomes play important roles in intercellular communication, both locally and systemically, by transporting their contents such as proteins, lipids and RNAs between cells. Of particular interest for controlled drug delivery is that cell-derived exosomes offer the possibilities of overcoming biological barriers, thereby allowing the incorporated gene and drug to reach targeted tissue, which have been considerable challenges for synthetic carriers. Great research efforts have been dedicated to developing exosome-based drug delivery systems for the treatment of inflammatory diseases, degenerative disorders and cancer. In this review, we will describe the structural and functional properties of exosomes and emphasize current advances in the therapeutic applications of exosomes as drug delivery vehicles, followed by a discussion on current challenges and future perspectives.

Activation of autophagy is a hallmark in tumor cells treated with chemotherapy, but the role of autophagy in acquired resistance of lung adenocarcinoma to cisplatin-based chemotherapy remains to be clarified. Our aim was to address that question by surveying the autophagic activity in parental lung adenocarcinoma cell line A549 and its 8-fold, more resistant subcell line, A549/DDP, which was obtained by treating cisplatin with increasing concentrations. A549/DDP and A549 cells were exposed to serum-free culture medium or ionizing radiation. To measure the stress-induced autophagy, LC3-II, as an autophagosome marker, was measured by immunofluorescence and Western blotting. To determine the effect of 3-MA, a known inhibitor of autophagy, on overcoming acquired cisplatin resistance, the MTT assay and flow cytometry were performed. Western blotting analysis demonstrated that LC3-II was increased in A549/DDP cells, compared with those of parental A549 cells, under stress conditions. Meanwhile, immunofluorescence staining showed that LC3-II protein was located mainly in the cytoplasm of A549/DDP. We also found that 3-MA can enhance the growth inhibition and apoptotic effect of cisplatin in acquired resistant cells (A549/DDP). Collectively, our results provide evidence that the upregulation of autophagy plays a major role in cisplatin resistance of A549/DDP cells.

Despite promising in vitro evidence for effective glioblastoma treatment, most drugs are hindered from entering the central nervous system because of the presence of the blood-brain barrier (BBB). Thus, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle. Extracellular vesicles (EVs), cell-derived membrane-encapsulated structures with diameters ranging from 50 to 1000 nm, have been explored as the drug delivery system to deliver their cargo to the brain tissue. Moreover, tumor targeting and selective drug delivery has been facilitated by engineering their parent cells to secrete modified EVs. However, the method suffers from many shortcomings including poor repeatability and complex and time-consuming operations. In this context, we present an easy-to-adapt and highly versatile methodology to modify EVs with an engineered peptide capable of recognition and eradication of glioma. On the basis of molecular recognition between phospholipids on EV lipid bilayer membranes and ApoA-I mimetic peptides, we have developed methotrexate (MTX)-loaded EVs functionalized with therapeutic [Lys-Leu-Ala (KLA)] and targeted [low-density lipoprotein (LDL)] peptides. In vitro experiments demonstrated that EVs decorated with LDL or KLA-LDL could obviously ameliorate their uptake by human primary glioma cell line U87 and permeation into three-dimensional glioma spheroids in contrast to blank EVs, and consequently, the treatment outcome of the payload is improved. Both ex vivo and in vivo imaging experiments revealed that peptide LDL could obviously promote EV extravasation across the BBB and distribution in the glioma site. Furthermore, compared with the mice administrated with MTX and MTX@EVs, MTX@EVs-KLA-LDL-treated mice showed the longest median survival period. In conclusion, functionalizing with the peptide onto EV surfaces may provide a substantial advancement in the application of EVs for selective target binding as well as therapeutic effects for brain tumor treatment.

We have demonstrated that mussel-inspired polydopamine can serve as an intermediate coating layer for covalently attaching oligonucleotides on nanostructures of diverse chemical nature, which are made possible by the universal adhesion and spontaneous reactivity of polydopamine. Our results have shown that polydopamine can strongly bond to representative nanoparticles (i.e., Au nanoparticles and magnetic polymer nanobeads) and form a thin layer of coating that allows for attachment of commercially available DNA with thiol or amine end functionality. The resulting DNA-nanoparticle conjugates not only show excellent chemical and thermal stability and high loading density of DNA, but the linked DNA also maintain their biological functions in directing cancer cell targeting and undergo DNA hybridization to form multifunctional magnetic core-plasmonic satellite assemblies. The generally applicable strategy opens new opportunities for easy adoption of DNA-nanoparticle conjugates for broad applications in biosensors and nanomedicine.

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Hypoxia is a hallmark of solid tumors, which presents a major obstacle to the effectiveness of radiation therapy. However, the function and the importance of molecular response have not been well defined. In the present study, hypoxia-induced autophagy and its effect on the response of breast cancer cells to ionizing radiation were examined. Results showed that hypoxic exposure induced a marked accumulation of autophagosomes accompanied by mRNA induction of the autophagy-related genes Beclin-1, Atg5, Atg7, and Atg12. The elevated autophagic activity was associated with increased radioresistance of tumor cells. Accordingly, blockade of autophagy by pharmacological inhibition or Beclin-1 small interfering RNA (siRNA) contributed to retardation of DNA double-strand breaks (DSB) repair and significant radiosensitization. Our data indicate that strategies designed to suppress autophagic activity may represent promising new therapies for sensitizing hypoxic breast cancer cells to ionizing radiation (IR).

Mounting evidence has suggested somatic mutations in the EGFR gene are associated with better responsiveness to EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Some, but not all, studies have reported that the mutations were more frequently observed in patients without a smoking history. To comprehensively address this issue, we performed a meta-analysis to evaluate the association between cigarette-smoking history and mutation of the EGFR gene in NSCLC. Twenty-six studies, involving 3,688 patients with NSCLC were included in the analysis. The pooled analysis shows that the incidence of EGFR mutations in NSCLC differs according to cigarette-smoking history. The odds ratio (OR) for the EGFR mutation in non-smokers relative to smokers was 4.829 (95% confidence interval [CI]: 3.598-6.482; P < 0.001). These data may assist clinicians in assessing the likelihood of EGFR mutations in patients with NSCLC when mutational analysis is not feasible.