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Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer’s disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.

A unique and complex microstructure underlies the diverse functions of the liver. Breakdown of this organization, as occurs in fibrosis and cirrhosis, impairs liver function and leads to disease. The role of integrin β1 was examined both in establishing liver microstructure and recreating it after injury. Embryonic deletion of integrin β1 in the liver disrupts the normal development of hepatocyte polarity, specification of cell–cell junctions, and canalicular formation. This in turn leads to the expression of transforming growth factor β (TGF-β) and widespread fibrosis. Targeted deletion of integrin β1 in adult hepatocytes prevents recreation of normal hepatocyte architecture after liver injury, with resultant fibrosis. In vitro, integrin β1 is essential for canalicular formation and is needed to prevent stellate cell activation by modulating TGF-β. Taken together, these findings identify integrin β1 as a key determinant of liver architecture with a critical role as a regulator of TGF-β secretion. These results suggest that disrupting the hepatocyte–extracellular matrix interaction is sufficient to drive fibrosis.

ABSTRACTPhase variation of Campylobacter fetussurface layer proteins (SLPs) occurs by inversion of a 6.2-kb DNA segment containing the unique sappromoter, permitting expression of a single SLP-encoding gene. Previous work has shown that theC. fetus sapinversion system is RecA dependent. When we challenged a pregnant ewe with a recAmutant of wild-typeC. fetus(strain 97-211) that expressed the 97-kDa SLP, 15 of the 16 ovine-passaged isolates expressed the 97-kDa protein. However, one strain (97-209) expressed a 127-kDa SLP, suggesting that chromosomal rearrangement may have occurred to enable SLP switching. Lack of RecA function in strains 97-211 and 97-209 was confirmed by their sensitivity to the DNA-damaging agent methyl methanesulfonate. Southern hybridization and PCR of these strains indicated that the aphAinsertion into recAwas stably present. However, Southern hybridizations demonstrated that in strain 97-209 inversion had occurred in the saplocus. PCR data confirmed inversion of the 6.2-kb DNA element and indicated that in these recAmutants the sapinversion frequency is reduced by 2 to 3 log10units compared to that in the wild type. Thus, although the major sapinversion pathway in C. fetusis RecA dependent, alternative lower-frequency, RecA-independent inversion mechanisms exist.