The Emerging Role of Exosome Nanoparticles in Regenerative Medicine
Harishkumar Madhyastha, Durgesh Nandini Chauhan in Nanopharmaceuticals in Regenerative Medicine, 2022
Exosomes are nanosized EVs (50–150 nm) originating from multivesicular bodies (MVBs). Various cells could release them into the extracellular environment through membrane fusion. These lipid bilayer nanovesicles are loaded with different cargos such as miRNA, DNA, RNA, lipids, and proteins. Exosomes are involved in different biological pathways such as intercellular communications, signal transferring, antigen presentation, and tumour progression. Their uptake occurs through endocytosis, direct fusion, or receptor–ligand interaction. Exosomes could be isolated and characterised by various methods such as Nanoparticle Tracking Analysis, Dynamic Light Scattering, Electron Microscopy, and Tunable Resistive Pulse Sensing (according to their size, density, surface charge, distinctive biomarkers, and membrane antigens).
Prevention of Restenosis by Gene Targeting
Eric Wickstrom in Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
The hemagglutinating virus of Japan (Sendai virus; HVJ), a member of the paramyxovirus family, has long been known to possess two viral coat proteins that enhance membrane fusion (Figure 1A) (Okada et al., 1961;Okada, 1993). Hemagglutinating neuroaminidase (HN) mediates viral particle binding to sialoglycoproteins or sialolipids on the cell surface. It then catalyzes the removal of sugar moieties from these surface molecules. After particle binding, the second protein, Fusion protein (F), induces membrane fusion via interaction with the lipid bilayer. The active form of F protein consists of two polypeptides, Fl and F2, produced by proteolytic cleavage of the inactive F0 form. Following cleavage, Fl and F2 remain associated, anchored by a disulfide bridge.
Stimulus-Secretion Coupling: Intracellular Proteins and Nucleotides
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
A molecular basis for synexin-driven calcium-dependent membrane fusion was presented by Pollard, Burns and Rojas (1988). Examination of cDNA clones for synexin showed that the molecule is similar to some other vesicle-aggregating proteins; but it does contain a unique, long, highly hydrophobic amino-terminal leader sequence followed by a characteristic 4-fold repeat that is homologous with repeats found in other members of the synexin gene family. The highly hydrophobic character of synexin seems consistent with information previously obtained that synexin is able to insert directly into interior bilayers prepared not only from purified phosphatidyl serine but also from biologic membranes. There also was evidence that synexin forms calcium-selective channels when the protein is applied to the cytosolic side of the plasma membrane. Therefore, the synexin molecule spans the membrane. From these and other data, Pollard et al. (1988) developed the concept that the fusion process may involve synexin forming a “hydrophobic bridge” between two fusing membranes. Lipid movement across this bridge may then be the material basis for fusion.
Biomimetic graphene oxide quantum dots nanoparticles targeted photothermal-chemotherapy for gastric cancer
Published in Journal of Drug Targeting, 2023
Ziwei Lei, Jialong Fan, Xiaojie Li, Yanhua Chen, Dazhi Shi, Hailong Xie, Bin Liu
Moreover, we carried out the membrane fusion experiment to prove the successful synthesis of the hybrid membrane (Figure 1(I)). The erythrocyte membranes and BGC-823 cell membranes were labelled with red and green fluorescent dyes, respectively, and the result showed that the red and green fluorescent overlapped and appeared as yellow, which proved the successful synthesis of the hybrid membrane. Figure 1(J) showed the ultraviolet absorption peaks of the erythrocyte membrane, tumour cell membrane, and hybrid membrane. Erythrocyte membrane and hybrid membranes showed similar characteristic absorption peaks. In addition, the membrane proteins of HM and pGOQD@HM NPs inherited the characteristic proteins of both RBCM and BGC-823M (Figure 1(K)), which proves the successful synthesis of hybrid membrane.
Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out
Published in Expert Opinion on Drug Delivery, 2023
Anindita De, Young Tag Ko
Furthermore, the hydration of ethanol molecules in ionizable LNPs post-treatment, both in the inner and outer lipid membranes, may result in lipid fusion in ionizable LNPs [73]. According to thermodynamics, the high concentration of ethanol in the ionizable LNPs causes an unstable lipid membrane, which promotes ionizable LNPs fusion and an increase in the particle size during long-term storage and causes instability [74]. While lowering the ethanol content is beneficial for short-term storage, it disrupts the structural orientation of the lipids in ionizable LNPs over time. After the rapid removal of the ethanol in the current microfluidics technology, the inside and outside of the ionizable LNPs are in equilibrium. Because of Fick’s law of diffusion, low-polarity tiny molecules like ethanol are carried across the lipid bilayer, although only 1–2% of the ethanol inside the ionizable LNPs formulation is capable of disrupting the lipid membrane. Diffused ethanol replaces water molecules on the surface of ionizable LNPs. As a result of the penetrating ethanol binding with the lipid head group, the lipid membrane forms an interdigital structure [73]. This interdigital structure, which has a larger surface area of hydrophobic groups than the typical lipid bilayer structure, is responsible for triggering membrane fusion. The fusing of the lipid membranes results in the leakage of the mRNA from ionizable LNPs [75].
Recent advances in the targeting of systemically administered non-viral gene delivery systems
Published in Expert Opinion on Drug Delivery, 2019
Ikramy A. Khalil, Yusuke Sato, Hideyoshi Harashima
Endosomal escape is the key and the rate-limiting process for the efficient delivery of nucleic acids to the cytosol. Membrane fusion or lipid mixing is the major mechanism for the endosomal escape of the LNPs. Especially; cationic lipids greatly facilitate electrostatic binding to anionic lipids in endosomal membranes, leading to membrane fusion. However, the strong cationic nature of the LNPs causes poor biodistribution and toxicity. Therefore, pH-sensitive cationic lipids have recently been developed to ensure both electrostatically neutral properties in the blood circulation for hepatocyte targeting via the ApoE-LDLR pathway and cationic properties in the acidic endosomal compartment for endosomal escape via membrane fusion. Zimmermann et al. first reported on in vivo hepatic gene silencing after the IV injection of siRNA-loaded LNPs containing a pH-sensitive cationic lipid, DLin-DMA both in mice and non-human primates [46]. Semple et al. designed a rational linker structure of DLin-DMA and identified a novel pH-sensitive cationic lipid, DLin-KC2-DMA (KC2), with improved fusogenisity [47]. The KC2-LNPs with optimized lipid composition showed approximately a 100-fold improvement of in vivo hepatic gene silencing activity compared to the DLin-DMA-LNPs with initial lipid composition.
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