Author: Read, Clarissa ; Glocker, Bernhard ; Schütz, Desiree ; Rauch-Wirth, Lena ; Münch, Jan ; Walther, Paul ; Groß, Rüdiger ; Müller, Janis A ; Rode, Sascha

Retroviral gene transfer is the preferred method for stable, long-term integration of genetic material into cellular genomes, commonly used to generate chimeric antigen receptor (CAR)-T cells designed to target tumor antigens. However, the efficiency of retroviral gene transfer is often limited by low transduction rates due to low vector titers and electrostatic repulsion between viral particles and cellular membranes. To overcome these limitations, peptide nanofibrils (PNFs) can be applied as transduction enhancers. Among these, PNFs derived from the 12-mer peptide EF-C are well-investigated and commercially available. EF-C PNFs enhance transduction by forming EF-C PNFs/virus complexes that overcome electrostatic repulsion through their polycationic surface and interaction with cellular protrusions. However, the safe application of PNFs as transduction enhancers in gene therapeutic applications requires a fundamental understanding of their transduction-enhancing mechanisms, uptake, and degradation. In this study, we demonstrate that EF-C PNFs induce plasma membrane invaginations, increasing the membrane surface for viral attachment and reducing the distance to the nuclear membrane, thereby facilitating viral entry and transport to the nucleus. Furthermore, we identified macropinocytosis as the main entry pathway for EF-C PNFs and their subsequent degradation by lysosomal peptidases. The lysosomal degradation of EF-C PNFs prevents their accumulation as amyloid deposits, mitigating potential side effects and supporting their safe use in clinical applications.

11 Apr 2025·ACS Infectious Diseases

Host–Pathogen Cellular Communication: The Role of Dynamin, Clathrin, and Macropinocytosis in the Uptake of Giardia-Derived Extracellular Vesicles

Article

Author: Marcilla, Antonio ; Bonato, Leticia ; Cortés, Alba ; Ramirez, Marcel I. ; Fucio, Sarah ; Sabatke, Bruna ; Rossi, Izadora V

Giardia intestinalis, a protozoan causing giardiasis, disrupts gastrointestinal health through complex host-parasite interactions. This study explores the differential uptake mechanisms of extracellular vesicles (EVs) derived from Giardia (gEVs), host cells (hEVs), and the host-parasite interaction (intEVs) in intestinal Caco-2 cells. Results show that intEVs are internalized more rapidly than gEVs and hEVs, underscoring their pivotal role in pathogenesis. To delineate uptake pathways, various endocytosis inhibitors were applied, and clathrin-mediated endocytosis inhibition using monodansylcadaverine (MDC) significantly reduced intEV and gEV uptake, confirming the role of clathrin-mediated endocytosis (CME). The use of dynasore, a dynamin inhibitor, strongly reduced the internalization of all EV types, demonstrating that uptake is dynamin-dependent. In contrast, methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts and caveolae-mediated pathways, had no effect on EV uptake, indicating that caveolae are not involved in this process. Furthermore, inhibition of Na⁺/H⁺ exchange and phosphoinositide 3-kinase activity, both essential for macropinocytosis, also led to a significant reduction in intEV internalization. These findings strongly support that gEVs are internalized primarily through a dynamin- and clathrin-dependent pathway, independent of caveolae and lipid rafts, but modulated by tyrosine kinase signaling and macropinocytosis. These insights into selective and comprehensive inhibition pathways offer promising therapeutic targets to mitigate giardiasis.

01 Apr 2025·Small

Dual‐Carriers of Tartary Buckwheat‐Derived Exosome‐Like Nanovesicles Synergistically Regulate Glucose Metabolism in the Intestine‐Liver Axis

Article

Author: Yang, Dan ; Midgley, Adam C. ; Liu, Wenguang ; Yang, Yongli ; Yao, Xiaolin ; Cao, Guifang ; Li, Guoliang ; Yi, Gaoyang ; He, Yujuan ; Li, Dan

AbstractThe utilization of plant‐derived exosome‐like nanovesicles (ELNs) as nanocarriers for oral delivery of bioactives has garnered significant attention. However, their distinctive lipid membrane composition may result in elevated membrane permeability within the gastrointestinal environment, leading to the leakage of carried bioactives. Inspired by the concept of projectile design, Tartary buckwheat‐derived ELNs (TB‐ELNs) based dual‐carriers are fabricated by loading chlorogenic acid (CGA) into the cores and bonding selenium nanoparticles (SeNPs) to the lipid membrane. The results indicate that SeNPs bond markedly augments the membrane rigidity, and therefore enhances the stability of TB‐ELNs and the retention rate of the loaded CGA during gastrointestinal digestion. In vitro and in vivo studies indicates that the TB‐ELNs based dual‐carriers are internalized by epithelial cells and transcytosis via the endoplasmic reticulum, and show the synergistic regulatory effect on high‐fat diet‐induced hyperglycemia in the intestine‐liver axis. These results may be attributed to the fact that SeNPs combination reduces the gastrointestinal degradation of the carried bioactives. Moreover, SeNPs with antioxidant property can protect ELNs and their carried bioactives from oxidative damage, thereby enhancing their biological activities. Collectively, this study offers a new strategy to develop highly efficient oral delivery systems for bioactives to alleviate hyperglycemia and diabetes.

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