Exosomes are circulating nanovesicular carriers of macromolecules, increasingly used for diagnostics and therapeutics. The ability to load and target patient-derived exosomes without altering exosomal surfaces is key to unlocking their therapeutic potential. We demonstrate that a peptide (CP05) identified by phage display enables targeting, cargo loading, and capture of exosomes from diverse origins, including patient-derived exosomes, through binding to CD63-an exosomal surface protein. Systemic administration of exosomes loaded with CP05-modified, dystrophin splice-correcting phosphorodiamidate morpholino oligomer (EXO) increased dystrophin protein 18-fold in quadriceps of dystrophin-deficient mdx mice compared to CP05-PMO. Loading CP05-muscle-targeting peptide on EXO further increased dystrophin expression in muscle with functional improvement without any detectable toxicity. Our study demonstrates that an exosomal anchor peptide enables direct, effective functionalization and capture of exosomes, thus providing a tool for exosome engineering, probing gene function in vivo, and targeted therapeutic drug delivery.
Hepatocellular carcinoma (HCC) remains a global challenge due to high morbidity and mortality rates and poor response to treatment. Immunotherapy, based on introduction of dendritic cells (DCs) activated by tumor cell lysates as antigens ex vivo, shows limited response rates in HCC patients. Here, we demonstrate that tumor cell-derived exosomes (TEXs), displaying an array of HCC antigens, can elicit a stronger immune response than cell lysates in vitro and in vivo. Significant tumor growth inhibition was achieved in ectopic and orthotopic HCC mice treated with TEX-pulsed DCs. Importantly, the tumor immune microenvironment was significantly improved in orthotopic HCC mice treated by TEX-pulsed DCs, demonstrated by increased numbers of T lymphocytes, elevated levels of interferon-c, and decreased levels of interleukin-10 and tumor growth factor-b in tumor sites. As expected, T cells played an essential role in the TEX-pulsed DC-mediated immune response. Notably, exosomes from HCC cells not only promoted HCC-specific cytolysis but also provided cross-protective effects against pancreatic cancer cells. Moreover, HCC-specific cytolysis, elicited by DCs pulsed with human HepG2 cellderived exosomes, was observed across different human HCC cells irrespective of human leukocyte antigen types. Conclusion: HCC TEXs can potently carry HCC antigens, trigger a strong DC-mediated immune response, and improve the HCC tumor microenvironment. (HEPATOLOGY 2016;64:456-472) R anked as the sixth most lethal malignancy, hepatocellular carcinoma (HCC) attracts significant attention due to its aggressive nature, high mortality rate, and low response rates to treatments in the clinic.(1) Although surgical resection can extend the life span of HCC patients, it is only amenable to early-stage HCC patients and has a high recurrence rate that is far from ideal. Chemotherapeutic or radiotherapeutic interventions such as sorafenib, transcatheter arterial chemoembolization, and radiofrequency ablation are intensively used in the clinic; however, the survival benefit is limited.(2) Therefore, other interventional approaches have been rigorously pursued. Among these, dendritic cell (DC)-based immunotherapy is a promising strategy with clinical studies in humans. (3)(4)(5) The first-in-human clinical trial among HCC patients demonstrated proof-of-concept evidence for DC-based immunotherapy with HCC cell lysates as antigens; however, the response rate was marginal and the efficacy was low, (5) necessitating further investigation into other immunotherapy options.Recently, the discovery of physiological roles of the exosome, a nanovesicle secreted by cells, as an intercellular courier of protein, messenger RNA, and micro-RNA, has garnered considerable interest.(6) Exosomes have been extensively studied for diagnostic purposes
High entropy alloys (HEAs) usually possess weak liquidity and castability, and considerable compositional inhomogeneity, mainly because they contain multiple elements with high concentrations. As a result, large-scale production of HEAs by casting is limited. To address the issue, the concept of eutectic high entropy alloys (EHEAs) was proposed, which has led to some promise in achieving good quality industrial scale HEAs ingots, and more importantly also good mechanical properties. In the practical large-scale casting, the actual composition of designed EHEAs could potentially deviate from the eutectic composition. The influence of such deviation on mechanical properties of EHEAs is important for industrial production, which constitutes the topic of the current work. Here we prepared industrial-scale HEAs ingots near the eutectic composition: hypoeutectic alloy, eutectic alloy and hypereutectic alloy. Our results showed that the deviation from eutectic composition does not significantly affect the mechanical properties, castability and the good mechanical properties of EHEAs can be achieved in a
Treating large established tumors is challenging for dendritic cell (DC)-based immunotherapy. DC activation with tumor cell-derived exosomes (TEXs) carrying multiple tumorassociated antigen can enhance tumor recognition. Adding a potent adjuvant, high mobility group nucleosome-binding protein 1 (HMGN1), boosts DCs' ability to activate T cells and improves vaccine efficiency. Here, we demonstrate that TEXs painted with the functional domain of HMGN1 (TEX-N1ND) via an exosomal anchor peptide potentiates DC immunogenicity. TEX-N1ND pulsed DCs (DC TEX-N1ND) elicit long-lasting antitumor immunity and tumor suppression in different syngeneic mouse models with large tumor burdens, most notably large, poorly immunogenic orthotopic hepatocellular carcinoma (HCC). DC TEX-N1ND show increased homing to lymphoid tissues and contribute to augmented memory T cells. Importantly, N1ND-painted serum exosomes from cancer patients also promote DC activation. Our study demonstrates the potency of TEX-N1ND to strengthen DC immunogenicity and to suppress large established tumors, and thus provides an avenue to improve DC-based immunotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.