Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin α v β 3 . Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

Both DNA and RNA can serve as powerful building blocks for bottom-up fabrication of nanostructures. A pioneering concept proposed by Ned Seeman 30 years ago has led to an explosion of knowledge in DNA nanotechnology. RNA can be manipulated with simplicity characteristic of DNA, while possessing noncanonical base-pairing, versatile function and catalytic activity similar to proteins. However, standing in awe of the sensitivity of RNA to RNase degradation has made many scientists flinch away from RNA nanotechnology. Here we report the construction of stable RNA nanoparticles resistant to RNase digestion. The chemically modified RNA retained its property for correct folding in dimer formation, appropriate structure in procapsid binding, and biological activity in gearing phi29 nanomotor to package viral DNA and producing infectious viral particles. Our results demonstrate that it is practical to produce RNase resistant, biologically active and stable RNA for application in nanotechnology.Keywords 2'-F modification; pRNA; RNase resistant; dimer formation; phi29 DNA-packaging nanomotor Living organisms produce a wide variety of highly-ordered or patterned structures such as smart nanomachines and elegant arrays that are made up of macromolecules to perform diverse biological functions. RNA and DNA share certain common features via their unique properties of strand complementarities and self-assembly, which can serve as powerful building blocks for bottom-up fabrication of nanostructures and nanodevices. A pioneering concept introduced by Ned Seeman 30 years ago has led to an explosion of knowledge in DNA nanotechnology.1 -3 RNA can be manipulated with simplicity characteristic of DNA, while possessing noncanonical base-pairing, versatile function, and catalytic activity similar * Address correspondence to: Peixuan Guo, 3125 Eden Ave. Rm#1436, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267, Phone: (513) Fax: (513) 558-6079, guopn@ucmail.uc.edu. # These authors contributed equally Supporting Information Available: RNase stability datas for 2'-F-C and 2'-F-U pRNA Aa', sucrose sedimentation profiles of pRNA in presence of Mg 2+ , Mn 2+ and Sr 2+ . This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript ACS Nano. Author manuscript; available in PMC 2012 January 25. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript to proteins. Typically, RNA molecules contain a large variety of single-stranded stem-loops for inter-and/or intra-molecular interactions. These loops can serve as mounting dovetails, and thus, external linking dowels might not be needed in fabrication and assembly. 4 -8 Although the concept of RNA nanotechnology has been developed for more than ten years6 , 9 -13 (for review, see14), standing in awe of RNA to RNase degradation has made many scientists hesitant to apply RNA nanotechnology. The popularity in the study of RNA nanostructure has emerged only recently as reflected in ...

Cell membrane-covered drug-delivery nanoplatforms have been garnering attention because of their enhanced biointerfacing capabilities that originate from source cells. In this top-down technique, nanoparticles (NPs) are covered by various membrane coatings, including membranes from specialized cells or hybrid membranes that combine the capacities of different types of cell membranes. Here, hybrid membrane-coated doxorubicin (Dox)-loaded poly(lacticco-glycolic acid) (PLGA) NPs (DPLGA@[RAW-4T1] NPs) were fabricated by fusing membrane components derived from RAW264.7(RAW) and 4T1 cells (4T1). These NPs were used to treat lung metastases originating from breast cancer. This study indicates that the coupling of NPs with a hybrid membrane derived from macrophage and cancer cells has several advantages, such as the tendency to accumulate at sites of inflammation, ability to target specific metastasis, homogenous tumor targeting abilities in vitro, and markedly enhanced multi-target capability in a lung metastasis model in vivo. The DPLGA@[RAW-4T1] NPs exhibited excellent chemotherapeutic potential with approximately 88.9% anti-metastasis efficacy following treatment of breast cancer-derived lung metastases. These NPs were robust and displayed the multi-targeting abilities of hybrid membranes. This study provides a promising biomimetic nanoplatform for effective treatment of breast cancer metastasis.

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