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Related Concept Videos

Lysosomes01:31

Lysosomes

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Lysosomes are membrane-enclosed spherical sacs derived from the Golgi apparatus. The most important function of the lysosome is degrading macromolecules and biological polymers that are released during membrane trafficking events such as the secretory, endocytic, autophagic, and phagocytic pathways. The degradation is carried out by several hydrolytic enzymes active in an acidic environment of the lysosomal lumen. These acid hydrolases are involved in cellular processes such as cell signaling,...
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Lysosomal Hydrolases01:22

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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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Maturation of Endosomes01:28

Maturation of Endosomes

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The early endosome containing internalized molecules matures through transformations in its location, morphology, intraluminal pH, and membrane protein composition. Together, these changes result in a more acidic late endosome that contains multiple intraluminal vesicles; therefore, the late endosome is also called a multivesicular body (MVB).
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Delivery Pathways to the Lysosome01:36

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Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
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In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
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Pinching-off of Coated Vesicles01:32

Pinching-off of Coated Vesicles

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Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
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Intralumenal Vesicles and Multivesicular Bodies01:38

Intralumenal Vesicles and Multivesicular Bodies

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Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
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Nanomechanical action opens endo-lysosomal compartments.

Yu Zhao1, Zhongfeng Ye1, Donghui Song1

  • 1Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.

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|October 20, 2023
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Researchers developed light-activated nanoscale machines for efficient intracellular delivery. These lipid-based machines break down endo-lysosomal compartments, improving biologic transport and enhancing anti-tumor immunity.

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Area of Science:

  • Biotechnology
  • Nanotechnology
  • Cell Biology

Background:

  • Endo-lysosomal escape is a major hurdle for delivering biologics like proteins and nucleic acids into cells.
  • Current intracellular delivery methods often suffer from low efficiency.

Purpose of the Study:

  • To design and fabricate a novel lipid-based nanoscale molecular machine for efficient cytosolic transport of biologics.
  • To utilize light-triggered nanomechanical action for destabilizing endo-lysosomal compartments.

Main Methods:

  • Co-assembly of azobenzene lipidoids with helper lipids to create light-responsive nanoscale machines.
  • Cellular uptake studies and observation of machine interaction with endo-lysosomal membranes.
  • Assessment of cargo (mRNA, Cre protein) delivery to the cytoplasm upon UV/Vis light irradiation.
  • Evaluation of antitumour activity in a melanoma mouse model using tumor antigens.

Main Results:

  • The lipid-based nanoscale molecular machines adhere to endo-lysosomal membranes after cellular entry.
  • Light-induced rotation-inversion of azobenzene lipidoids destabilizes membranes, facilitating cargo release into the cytoplasm.
  • Cytosolic transport efficiency was improved approximately 2.1-fold compared to conventional systems.
  • Delivery of tumor antigens into dendritic cells induced significant antitumour activity in vivo.

Conclusions:

  • Light-activated lipid-based nanoscale molecular machines offer a novel strategy for efficient intracellular delivery.
  • This technology enhances cytosolic transport of biologics and holds promise for immunotherapy applications.
  • The nanomechanical action provides a mechanism for overcoming endo-lysosomal barriers.