EXTRACELLULAR VESICLES TARGETING DENDRITIC CELLS AND USES THEREOF
The present disclosure relates to modified extracellular vesicles, e.g., exosomes, comprising a targeting moiety, wherein the targeting moiety can specifically bind to markers expressed on distinct immune cells (e.g., dendritic cells). Also provided herein are methods for using the exosomes to treat and/or prevent a range of medical disorders.
1 . An extracellular vesicle (EV) comprising an exogenous targeting moiety that specifically binds to a marker for a dendritic cell.
2 . The EV of claim 1 , wherein the marker is present only on the dendritic cell.
3 . The EV of claim 1 , wherein the dendritic cell comprises a plasmacytoid dendritic cell (pDC), a myeloid/conventional dendritic cell 1 (cDC1), a myeloid/conventional dendritic cell 2 (cDC2), or any combination thereof.
4 . (canceled)
5 . The EV of claim 1 , wherein the marker comprises a C-type lectin domain family 9 member A (Clec9a) protein, a dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), CD207, CD40, Clec6, dendritic cell immunoreceptor (DCIR), DEC-205, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), MARCO, Clec12a, DC-asialoglycoprotein receptor (DC-ASGPR), DC immunoreceptor 2 (DCIR2), Dectin-1, macrophage mannose receptor (MMR), BDCA-1 (CD303, Clec4c), Dectin-2, Bst-2 (CD317), or any combination thereof.
6 . The EV of claim 5 , wherein the marker comprises (i) an epitope in the Clec9a protein, or (ii) a C-type lectin like domain.
7 - 10 . (canceled)
11 . The EV of claim 1 , wherein the exogenous targeting moiety comprises a peptide, an antibody or an antigen-binding fragment thereof, a chemical compound, or any combination thereof.
12 - 15 . (canceled)
16 . The EV of claim 1 , wherein the EV comprises a scaffold protein linking the exogenous targeting moiety to the EV.
17 . The EV of claim 16 , wherein the scaffold protein is a Scaffold X protein.
18 . The EV of claim 17 , wherein the Scaffold X protein comprises prostaglandin F2 receptor negative regulator (the PTGFRN protein); basigin (the BSG protein); immunoglobulin superfamily member 2 (the IGSF2 protein); immunoglobulin superfamily member 3 (the IGSF3 protein); immunoglobulin superfamily member 8 (the IGSF8 protein); integrin beta-1 (the ITGB1 protein); integrin alpha-4 (the ITGA4 protein); 4F2 cell-surface antigen heavy chain (the SLC3A2 protein); a class of ATP transporter proteins (the ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B3, ATP2B1, ATP2B2, ATP2B3, ATP2B4 proteins), CD13, aminopeptidase N (ANPEP), neprilysin (membrane metalloendopeptidase; MME), ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), neuropilin-1 (NRP1), CD9, CD63, CD81, PDGFR, GPI anchor proteins, lactadherin, LAMP2, LAMP2B, a fragment thereof, or any combination thereof.
19 . (canceled)
20 . (canceled)
21 . The EV of claim 1 , further comprising a Scaffold Y protein.
22 . The EV of claim 21 , wherein the Scaffold Y protein comprises myristoylated alanine rich Protein Kinase C substrate (the MARCKS protein), myristoylated alanine rich Protein Kinase C substrate like 1 (the MARCKSL1 protein), brain acid soluble protein 1 (the BASP1 protein), a fragment thereof, and or any combination thereof.
23 - 45 . (canceled)
46 . The EV of claim 1 , further comprising a therapeutic molecule, an immune modulator, an adjuvant, or any combination thereof.
47 - 57 . (canceled)
58 . The EV of claim 1 , wherein the EV is an exosome.
59 . The EV of claim 46 , wherein the therapeutic molecule is associated with a Scaffold X or a Scaffold Y protein.
60 - 64 . (canceled)
65 . A pharmaceutical composition comprising the EV of claim 1 and a pharmaceutically acceptable carrier.
66 . A cell that produces the EV of claim 1 .
67 . (canceled)
68 . A kit comprising the EV of claim 1 and instructions for use.
69 . A method of making EVs comprising culturing the cell of claim 66 under a suitable condition and obtaining the EVs.
70 . A method of preventing or treating a disease in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 65 .
71 . The method of claim 70 , wherein the disease is selected from a cancer, a hemophilia, diabetes, a growth factor deficiency, an eye disease, a graft-versus-host disease (GvHD), an autoimmune disease, a gastrointestinal disease, a cardiovascular disease, a respiratory disease, an allergic disease, a degenerative disease, an infectious disease, fibrotic diseases, or any combination thereof.
72 - 74 . (canceled)