Composition for delivering functional substance and uses thereof

Abstract

The present invention relates to a composition for delivering functional substances and uses thereof. The composition for delivering functional substances using non-vesicular extracellular particles according to the present invention can effectively load genetic materials such as proteins, mRNA, and / or pDNA and efficiently deliver same to cells, and thus can be used as a pharmaceutical composition or a functional cosmetic composition for treating diseases.

Description

Still another object of the present invention is to provide a use of a non-vesicular extracellular particle for delivering a functional substance. The technical problems to be achieved according to the technical idea of the invention disclosed in the present specification are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. [Advantageous Effects] According to one example of the present invention, the composition for delivering a functional substance using the non-vesicular extracellular particle of the present invention can effectively load proteins and genetic materials such as mRNA and / or pDNA, and can efficiently deliver the same to cells, and thus can be used as a pharmaceutical composition for treating a disease or as a functional cosmetic composition. [Brief Description of Drawings] FIG. 1 shows extracellular particles and a subclassification system thereof. FIG. 2 shows a preparation process of subclassified substances of extracellular particles. FIG. 3 shows confirmation of protein marker expression of supermeres distinguished from exomeres and small extracellular vesicles. FIG. 4 shows results confirming that, as a result of treating recipient cells with extracellular particles isolated from cells into which eGFP was transduced, expression of the eGFP protein was induced in the recipient cells regardless of whether RNase pretreatment was performed. FIG. 5 shows results confirming that, among extracellular particles isolated from cells into which eGFP was transduced, particles capable of inducing eGFP expression in recipient cells were small extracellular particles, not large extracellular vesicles. FIG. 6 shows results confirming that, among small extracellular particles isolated from cells into which eGFP was transduced, a main carrier capable of effectively inducing eGFP expression in recipient cells was a non-vesicular extracellular particle, not a small extracellular vesicle. FIG. 7 shows results confirming that, regardless of the type of transduced plasmid, non-vesicular extracellular particles are main carriers capable of inducing eGFP expression in recipient cells more effectively than small extracellular vesicles and the entire extracellular particle group. FIG. 8 shows results confirming that, regardless of the type of transduced plasmid, among non-vesicular extracellular particles, supermeres are main carriers capable of inducing eGFP expression in recipient cells more effectively than small extracellular vesicles and exomeres. FIG. 9 shows results confirming the amount of eGFP-mRNA endogenously present in small extracellular vesicles, exomeres, and supermeres isolated from cells into which eGFP was transduced. FIG. 10 shows results confirming the expression level of eGFP protein endogenously present in small extracellular vesicles, exomeres, and supermeres isolated from cells into which eGFP was transduced. FIG. 11 shows results demonstrating that supermeres isolated from cells into which eGFP was transduced are main carriers capable of delivering eGFP mRNA into recipient cells more effectively than small extracellular vesicles and exomeres. FIG. 12 shows results demonstrating that supermeres isolated from cells into which eGFP was transduced are main carriers that induce eGFP protein expression in recipient cells more effectively than small extracellular vesicles and exomeres. FIG. 13 shows results confirming intracellular internalization of supermeres through lipid rafts (FIGS. 13a and 13b: results of Cy5.5 expression in recipient cells at 30 minutes, 3 hours, and 24 hours after treating the recipient cells with each drug and supermeres; FIG. 13c: changes in the ratio of cells containing supermeres stained with Cy5.5 for 24 hours after treating recipient cells with each drug and supermeres). FIG. 14 shows results confirming that supermeres can deliver exogenous eGFP mRNA to recipient cells more effectively than small extracellular vesicles and exomeres. FIG. 15 shows results confirming intracellular delivery of GFP pDNA using supermeres. FIG. 16 shows results in which GFP fluorescence expressed in intestinal tissue was observed by ex vivo imaging in order to compare intestinal exogenous eGFP mRNA delivery and protein translation efficiency of supermeres and lipid nanoparticles after intravascular injection. FIG. 17 shows results confirming eGFP protein expression in intestinal tissue in order to compare intestinal exogenous eGFP mRNA delivery and protein translation efficiency of supermeres and lipid nanoparticles after intravascular injection. FIG. 18 shows results confirming distribution by organ after supermeres and small extracellular vesicles derived from HEK293FT cells were fluorescently labeled and intravascularly injected, and a predetermined time had elapsed. FIG. 19 is an image comparing accumulation by organ of HEK293FT cell-derived supermeres and small extracellular vesicles by isolating only liver, spleen, and kidney tissues in the experiment of FIG. 18. FIG. 20 shows results confirming distribution by organ after supermeres and small extracellular vesicles derived from human bone marrow-derived mesenchymal stem cells (MSC) were fluorescently labeled, and intravascularly injected and a predetermined time elapsed. FIG. 21 shows results confirming the amount of a functional substance expressed in supermeres isolated from cells transduced in a form in which TGFBI, which is a supermere marker protein, and a functional substance of interest were fused. [Detailed Description of Preferred Embodiments] This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention should not be construed as being limited by the specific description described below. In addition, those skilled in the art can recognize or confirm many equivalents to specific aspects of the present invention described in the present invention using only ordinary experimentation. In addition, such equivalents should be understood as being included in the present invention. In addition, throughout the present specification, a number of papers and patent documents are referenced, and citations thereof are indicated. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety, so that the level of the technical field to which the present specification belongs and the contents of the present specification are more clearly described. The present invention is based on the confirmation of a novel use of a non-vesicular extracellular particle (NVEP). Conventionally, cells release vesicles of various membrane types according to the extracellular environment. Generally, such released vesicles are referred to as extracellular vesicles (EVs), and the extracellular vesicles enable exchange of substances, such as proteins, lipids, and genetic materials, between cells and act as mediators of physiological / pathological signaling, and thus various studies using the same are being conducted. However, studies using non-vesicular extracellular particles, particularly exomeres and supermeres (Supernatants of Exomeres), are still very limited. In particular, studies on a composition for delivering a functional substance using non-vesicular extracellular particles are insufficient. The present invention is based on newly demonstrating that a non-vesicular extracellular particle, particularly a supermere, efficiently loads a functional substance, for example, an external gene, and efficiently delivers the same to a cell. Specifically, one aspect of the present invention provides a composition for delivering a functional substance, comprising a non-vesicular extracellular particle (NVEP) as an active ingredient. As used herein, the term “extracellular particle (EP)” refers to any particle naturally derived from a cell. The extracellular particles are divided into vesicular and non-vesicular particles, and vesicular particles include extracellular vesicles (EVs). The extracellular vesicle refers to any natural nanoparticle consisting of lipid bilayers derived from a cell and is distinguished from the non-vesicular extracellular particle (NVEP) used as an active ingredient in the present invention. The extracellular vesicles are divided into large extracellular vesicles (large EVs) having a large average diameter size of 200 nm or more, and small extracellular vesicles (small EVs) having an average diameter size of 200 nm or less. As used herein, the term non-vesicular extracellular particle (NVEP) refers to a natural nanoparticle derived from a cell, in which a lipid bilayer is not present. The non-vesicular extracellular particles are classified into exomeres, which are naturally occurring nanoparticles having a size of 50 nm or less and lacking a lipid bilayer, and supermeres (Supernatants of Exomeres), which are included in a supernatant (sup) obtained by ultracentrifugation of exomeres. The supermere is characterized in that it is distinguished from an extracellular vesicle or an exomere in terms of size, RNA and protein profiles, and total RNA quantity. In addition, the supermere may be distinguished from an extracellular vesicle or an exomere using a marker. For example, the marker is a protein specifically present in a large amount in a supermere, and may be referred to as a “supermere marker protein”. In one specific embodiment, the supermere marker protein may be one or more selected from transforming growth factor beta-induced (TGFBI), enolase-1 (ENO1), enolase-2 (ENO2), heat shock 70 kDa protein 13 (HSPA13), glucose-6-phosphate isomerase (GPI), lactate dehydrogenase A (LDHA), triosephosphate isomerase 1 (TPI1), hexokinase 1 (HK1), malate dehydrogenase 1 (MDH1), nucleobindin-1 (NUCB1), and protein disulfide isomerase family A member 4 (PDIA4), but is not limited thereto. In one specific embodiment, the supermere may be distinguished by the marker regardless of the type of cell of origin. The cell may be, for example, a human embryonic kidney cell (HEK cell) or a stem cell, but is not limited thereto. In one embodiment of the present invention, the stem cell may be an embryonic stem cell (ESC), an induced pluripotent stem cell (iPSC), or an adult stem cell. In one embodiment of the present invention, the adult stem cell may be selected from the group consisting of a mesenchymal stem cell, a human tissue-derived mesenchymal stromal cell, a human tissue-derived mesenchymal stem cell, a multipotent stem cell, and an amniotic epithelial cell. In one embodiment of the present invention, the mesenchymal stem cell may be derived from one or more tissues selected from the group consisting of umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amnion, and placenta. In one embodiment of the present invention, the non-vesicular extracellular particle may be a supermere, but is not limited thereto. The extracellular particle and the subclassification system thereof are shown in FIG. 1. In one embodiment of the present invention, the “delivering a functional substance” may be delivery of a functional substance possessed by a donor cell to a recipient cell, an organ, or a subject, or may be delivery of a functional substance present outside a cell or intended to be delivered to a target to which delivery is desired by the composition for delivering a functional substance of the present invention, for example, a recipient cell, an organ, or a subject, but is not limited thereto. In one embodiment of the present invention, the functional substance may be in a protein form. In one embodiment of the present invention, the functional substance may be in an RNA form. In one embodiment of the present invention, the functional substance may be in a DNA form. The functional substance may be, for example, a gene. In one specific embodiment, the functional substance may be selected from the group consisting of mRNA, shRNA, miRNA, gRNA, pri-miRNA, pre-miRNA, circular RNA, piRNA, tRNA, rRNA, snRNA, lncRNA, ribozyme, minicircle DNA, or plasmid DNA (pDNA), but is not limited thereto. In the present invention, the genes may exist in nature or may be synthesized, and may exist in various sizes from oligonucleotides to chromosomes. These genes may be derived from humans, animals, plants, bacteria, viruses, etc., but are not limited thereto. For example, the gene may be a newly synthesized synthetic gene, and is included without limitation as long as the gene can be loaded in the non-vesicular extracellular particle of the present invention and delivered as a gene synthesized according to various desired purposes, such as a gene as a drug, a gene as an inhibitor, or a gene having a cosmetic effect. The gene may be obtained using methods known in the art. In another embodiment of the present invention, the functional substance may include a protein. The protein may be an antibody or a fragment thereof having immunological activity, an intrabody, a single-chain variable fragment, an affibody, an enzyme, a transporter, a tumor suppressor, a viral or bacterial inhibitor, a cellular component protein, a DNA- or RNA-binding protein, a DNA repair inhibitor, a nuclease, a proteinase, an integrase, a transcription factor, a growth factor, an apoptosis inhibitor and inducer, a toxin, a structural protein, a neurotrophic factor, a membrane transporter, a nucleotide- binding protein, a heat shock protein, or a CRISPR-related protein, but is not limited thereto. In still another embodiment of the present invention, the functional substance may include a drug. The drug is not particularly limited as long as it can move into cells and exert an effect. Such a drug may be any drug consisting of a low-molecular compound such as a cytotoxic anticancer agent, or any biopharmaceutical such as recombinant protein, siRNA, ASO, mRNA, gRNA, or tRNA, and may be, in terms of efficacy, an antiinflammatory agent, an analgesic, an anti-arthritic agent, an antispasmodic agent, an antidepressant, an antipsychotic drug, a tranquilizer, an anxiolytic agent, a narcotic antagonist, an anti-Parkinson's disease drug, a cholinergic agonist, an anticancer agent, an angiogenesis inhibitor, an immunosuppressant, an immunostimulant, an antiviral agent, an antibiotic, an appetite suppressant, an anticholinergic agent, an antihistamine, an antimigraine agent, a hormone agent, a coronary vasodilator, a vasodilator, a contraceptive, an antithrombotic agent, a diuretic, an antihypertensive agent, a therapeutic agent for cardiovascular disease, a diagnostic agent such as a contrast agent, or the like, but is not limited thereto. The functional substance may be a therapeutic agent, a diagnostic agent, or a combination thereof. The functional substance may be selected from the group consisting of a nucleic acid, a protein, a polypeptide, a low-molecular compound, and a carbohydrate. The functional substance may include one or more nucleic acid sequences, one or more polypeptides, a combination of a nucleic acid sequence and / or a polypeptide, one or more organelles, and any combination thereof. In some embodiments, the functional substance may include one or more cellular components. In some embodiments, the functional substance may include one or more cytoplasmic and / or nuclear components. The functional substance includes nucleic acids, for example, transcription factors, DNA, nDNA (nuclear DNA), mtDNA (mitochondrial DNA), protein coding DNA, genes, operons, chromosomes, genomes, transposons, retrotransposons, viral genomes, introns, exons, modified DNA, ssDNA (single-stranded DNA), dsDNA (double-stranded DNA), mRNA (messenger RNA), sgRNA (single guide RNA), gRNA (guide RNA), pegRNA (prime editing guide RNA), tRNA (transfer RNA), modified RNA, microRNA (miRNA), siRNA (small interfering RNA), tmRNA (transfer messenger RNA), rRNA (ribosomal RNA), mtRNA (mitochondrial RNA), snRNA (small nuclear RNA), small nucleolar RNA (snoRNA), SmY RNA (mRNA trans-splicing RNA), TERC (telomerase RNA component), aRNA (antisense RNA), cis-NAT (cis-natural antisense transcript), CRISPR RNA (crRNA), tracrRNA (trans-activating CRISPR RNA), lncRNA (long noncoding RNA), piRNA (piwi-interacting RNA), tasiRNA (trans-acting siRNA), eRNA (enhancer RNA), satellite RNA, pcRNA (protein-coding RNA), RNAi (interfering RNA), circRNA (circular RNA), reprogramming RNA, aptamers, antisense oligonucleotides, shRNA (short hairpin RNA), dsRNA (double-stranded RNA), antisense RNA, ribozymes, and any combination thereof. In some embodiments, the nucleic acid is a wild-type nucleic acid. In some embodiments, the nucleic acid is a mutant nucleic acid. In some embodiments, the nucleic acid is a fusion or chimera of a plurality of nucleic acid sequences. In some embodiments, the nucleic acid may contain a nuclear localization signal (NLS) capable of increasing nuclear editing efficacy. The NLS is an amino acid sequence that tags a protein to be introduced into a cell nucleus through nuclear transport. In some embodiments, the functional substance may include a nucleic acid. For example, the substance of interest may include RNA that enhances the expression of an endogenous protein (for example, in some embodiments, endogenous to a producing cell of lipid bilayer particles, and in some embodiments, endogenous to a target cell), or siRNA or miRNA that inhibits the expression of an endogenous protein. In some embodiments, the functional substance includes a polypeptide, for example, an enzyme, a structural polypeptide, a signaling polypeptide, a regulatory polypeptide, a transport polypeptide, a sensory polypeptide, a motor polypeptide, a defense polypeptide, a storage polypeptide, a transcription factor, an antibody, a cytokine, a hormone, a catabolic polypeptide, an anabolic polypeptide, a proteolytic polypeptide, a metabolic polypeptide, a kinase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, an enzyme regulator polypeptide, a protein-binding polypeptide, a lipid-binding polypeptide, a membrane fusion polypeptide, a cell differentiation polypeptide, an epigenetic polypeptide, a cell death polypeptide, a nuclear transport polypeptide, a nucleic acid-binding polypeptide, a reprogramming polypeptide, a DNA editing polypeptide, a DNA repair polypeptide, a DNA recombination polypeptide, a transposase polypeptide, a DNA integration polypeptide, a targeted endonuclease (for example, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), Cas9 and homologs thereof), a recombinase, and any combination thereof. In some embodiments, the protein is a wild-type protein. In some embodiments, the protein is a mutant protein. In some embodiments, the protein is a fusion or chimeric protein. In some embodiments, the functional substance includes a small molecule, for example, ions (for example, Ca2+, Cl-, Fe2+), carbohydrates, lipids, reactive oxygen species, reactive nitrogen species, isoprenoids, signaling molecules, heme, polypeptide cofactors, electron acceptor compounds, electron donor compounds, metabolites, ligands, and any combination thereof. In some embodiments, the functional substance includes a mixture of proteins, nucleic acids, or metabolites, for example, multipolypeptides, multiple nucleic acids, or multi-small molecules; a combination of nucleic acids, polypeptides, and small molecules; a ribonucleoprotein complex (for example, a Cas9-gRNA complex); multiple transcription factors, multiple epigenetic factors, or reprogramming factors (for example, Oct4, Sox2, cMyc, and Klf4); multiple regulatory RNAs; and any combination thereof. In some embodiments, the functional substance includes one or more organelles, for example, chondriosomes, mitochondria, lysosomes, nuclei, cell membranes, cytoplasm, endoplasmic reticulum, ribosomes, vacuoles, endosomes, spliceosomes, polymerases, capsids, acrosomes, autophagosomes, centrosomes, glycosomes, glyoxysomes, hydrogenosomes, melanosomes, mitosomes, myofibrils, cnidocysts, peroxisomes, proteasomes, vesicles, stress granules, networks of organelles, and any combination thereof. In some embodiments, the functional substance may be a DNA-digesting agent capable of digesting DNA. This means an agent capable of cleaving a bond between nucleotide subunits of a nucleic acid (e.g., a phosphodiester bond). In one embodiment, the DNA-digesting agent is a nuclease. A nuclease is an enzyme that hydrolyzes nucleic acids. Nucleases may be classified as endonucleases or exonucleases. An endonuclease is a group of enzymes that catalyze hydrolysis of bonds between nucleic acids inside a DNA or RNA molecule. An exonuclease is a group of enzymes that catalyze hydrolysis of single nucleotides at the end of a DNA or RNA chain. Nucleases may also be classified according to whether they specifically digest DNA or RNA. Nucleases that specifically catalyze hydrolysis of DNA may be referred to as deoxyribonucleases or DNases, whereas nucleases that specifically catalyze hydrolysis of RNA may be referred to as ribonucleases or RNases. Some nucleases are specific for single-stranded or double-stranded nucleic acid sequences. Some enzymes have both exonuclease and endonuclease properties. In addition, some enzymes can digest both DNA and RNA sequences. In some embodiments, the functional substance may be an endonuclease. Nonlimiting examples of the endonuclease may include, but are not limited to, zinc finger nuclease (ZFN), a ZFN dimer, ZFNickase, transcription activator-like effector nuclease (TALEN), meganuclease, or an RNA-guided DNA endonuclease (e.g., a CRISPR / Cas system). In one embodiment, the endonuclease may be engineered, chimerized, or isolated from an organism. The endonuclease may be engineered to recognize a specific DNA sequence, for example, by mutagenesis. In some embodiments, the functional substance may be an RNA-guided DNA endonuclease (for example, a CRISPR-Cas system). In particular, the lipid bilayer particle may further include gRNA, crRNA, tracrRNA, etc. “gRNA”, “guide RNA”, and “CRISPR guide sequence” may be used interchangeably and mean a nucleic acid comprising a sequence that determines the specificity of a Cas DNA-binding protein of a CRISPR / Cas system. The gRNA hybridizes (partially or completely complementarily) to a target nucleic acid sequence of a host cell genome. The gRNA or portion thereof that hybridizes to the target nucleic acid may have a length of 15 to 25 nucleotides, 18 to 22 nucleotides, or 19 to 21 nucleotides. In some embodiments, the length of the gRNA sequence that hybridizes to the target nucleic acid is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. A “scaffold sequence”, also referred to as tracrRNA (trans-activating CRISPR RNA), means a nucleic acid sequence that recruits a Cas endonuclease to a target nucleic acid bound (hybridized) to a complementary gRNA sequence. In some embodiments, the gRNA sequence does not include the scaffold sequence, and the scaffold sequence is expressed as a separate transcript. In these embodiments, the gRNA sequence further includes an additional sequence that is complementary to a portion of the scaffold sequence, binds (hybridizes) to the scaffold sequence, and functions to recruit the endonuclease to the target nucleic acid. In some embodiments, the RNA-guided DNA endonuclease is a Cas enzyme, that is, a CRISPR-associated endonuclease. The Cas enzyme may be a naturally occurring Cas enzyme or a functional derivative thereof. In certain embodiments, the Cas enzyme may include one or more mutations. The Cas enzyme may be a type II, type I, type III, type IV, or type V CRISPR system enzyme. In some embodiments, the Cas enzyme is a Cas9 enzyme (also known as Cas5, Csn1, or Csx12). Cas9 may be wild-type or mutant. In some embodiments, the endonuclease is a Cas9 homologue or orthologue. Cas9 may be any variant disclosed in U.S. Patent Publication No. US 2014 / 0068797 A1, incorporated herein by reference. In one embodiment, the Cas9 enzyme may be type II-A, type II-B, or type II-C. In one embodiment, the Cas9 enzyme may be derived from various species. Non-limiting examples of Cas9 enzymes may include Cas9 derived from Streptococcus pyogenes (S. pyogenes), Streptococcus pneumoniae (S. pneumoniae), Staphylococcus aureus, Neisseria meningitidis, Streptococcus thermophilus (S. thermophilus), or Treponema denticola. Cas9 enzymes may also be derived from microorganisms of the genera Corynebacterium, Sutterella, Legionella, Treponema, Filifactor, Eubacterium, Streptococcus, Lactobacillus, Mycoplasma, Bacteroides, Flaviivola, Flavobacterium, Sphaerochaeta, Azospirillum, Gluconacetobacter, Neisseria, Roseburia, Parvibaculum, Staphylococcus, Nitratifractor, Mycoplasma, or Campylobacter. In some embodiments, the Cas enzyme may be Cas9, Cpf1, C2c1, C2c2, C2c3, Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas10, Csy1, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, Csf3, Csf4, a homologue thereof, an orthologue thereof, or a variant thereof. In some embodiments, the functional substance may include a diagnostic agent, but is not limited to, a radioactive tracer or radionuclide used in positron emission tomography (PET) (for example, carbon-11, nitrogen-13, oxygen-15, and fluorine-18). These agents may be more accurately delivered to a tissue of interest by loading them into engineered extracellular particles that artificially or naturally target the tissue of interest, i.e., the tissue being scanned, thereby reducing off-target delivery of the diagnostic agent. In some embodiments, the functional substance may be a targeting moiety. In some embodiments, the non-vesicular extracellular particle may further include at least one targeting moiety. In some embodiments, the targeting moiety may be used to target the non-vesicular extracellular particle to a specific organ, tissue, or cell for delivery of the functional substance using the non-vesicular extracellular particle. In certain examples, the targeting moiety may bind to a marker (or target molecule) expressed in a cell or a cell population. In certain embodiments, the marker may be expressed in various cell types, for example, all antigen-presenting cells (for example, dendritic cells, macrophages, and B lymphocytes). In some examples, the marker may be expressed only in a specific cell population (e.g., dendritic cells). Non-limiting examples of markers expressed in a specific cell population (e.g., dendritic cells) include C-type lectin domain family 9 member A (CLEC9A) protein or 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), and any combination thereof. In some embodiments, the targeting moiety may be an antibody or an antigenbinding fragment thereof. Antibodies and antigen-binding fragments thereof include whole antibodies, polyclonal, monoclonal, and recombinant antibodies, and fragments thereof, and may further include single-chain antibodies, humanized antibodies, murine antibodies, chimeric, mouse-human, mouse-primate, and primate-human antibodies. Monoclonal antibodies, anti-idiotype antibodies, antibody fragments (for example, scFv, (scFv)2, Fab, Fab' and F(ab')2, F(ab1)2, Fv, dAb, and Fd fragments), diabodies, and antibody-related polypeptides are included. Antibodies and antigen-binding fragments thereof may include bispecific antibodies and multispecific antibodies as long as they exhibit a desired biological activity or function. In one embodiment of the present invention, the supermere may have improved functional substance delivery ability relative to extracellular vesicles or exomeres. In one embodiment of the present invention, the supermere may be accumulated in the liver in a smaller amount relative to extracellular vesicles or exomeres. In one embodiment of the present invention, the supermere may be accumulated in the spleen in a smaller amount relative to extracellular vesicles or exomeres. In one embodiment of the present invention, the supermere may be accumulated in the kidney in a larger amount relative to extracellular vesicles or exomeres. In one embodiment of the present invention, the composition may comprise a vector comprising the gene. In the present invention, the term “vector” means a carrier into which a nucleic acid sequence can be inserted for introduction into a cell capable of replicating the nucleic acid sequence. The nucleic acid sequence may be exogenous or heterologous. Examples of the vector include, but are not limited to, plasmids, cosmids, and viruses (for example, bacteriophages). In one embodiment of the present invention, the vector includes, but is not limited to, a plasmid vector, a cosmid vector, a bacteriophage vector, a viral vector, etc. A suitable vector comprises a signal sequence or leader sequence for membrane targeting or secretion in addition to expression control elements such as a promoter, operator, start codon, stop codon, polyadenylation signal, and enhancer, and may be prepared in various ways depending on the purpose. The promoter of the vector may be constitutive or inducible. In one specific embodiment, the vector may be pcDNA3.1, pcDNA3.4, pMXs-IRES, pDisplay, pRG2-GG, prp[exp], or pCMV, but is not limited thereto. Another aspect of the present invention provides a composition for delivering a functional substance, comprising a non-vesicular extracellular particle marker protein and a non-vesicular extracellular particle comprising a functional substance of interest. The terms “non-vesicular extracellular particle”, “functional substance”, and “delivering a functional substance” are as described above. In one embodiment of the present invention, the functional substance of interest may be in a form fused with the non-vesicular extracellular particle marker protein. In one embodiment of the present invention, the non-vesicular extracellular particle may be a supermere. In one embodiment of the present invention, the functional substance of interest may be in a form fused with a supermere marker protein. In one embodiment of the present invention, the supermere marker protein may be one or more selected from the group consisting of transforming growth factor beta induced (TGFBI), enolase-1 (ENO1), enolase-2 (ENO2), heat shock 70 kDa protein 13 (HSPA13), glucose-6-phosphate isomerase (GPI), lactate dehydrogenase A (LDHA), triosephosphate isomerase 1 (TPI1), hexokinase 1 (HK1), malate dehydrogenase 1 (MDH1), nucleobindin-1 (NUCB1), protein disulfide isomerase family A member 4 (PDIA4), a fragment thereof, a variant thereof, a variant of a fragment thereof, and a fragment of a variant thereof, but is not limited thereto. In addition, another aspect of the present invention provides a pharmaceutical composition comprising the composition for delivering a functional substance. The pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. As the pharmaceutically acceptable carrier, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these components may be used, and, if necessary, other conventional additives such as an antioxidant, buffer, and bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets. Therefore, the pharmaceutical composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, or the like. These formulations may be prepared by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and may be formulated into various formulations according to each disease or component. The composition of the present invention is administered in a pharmaceutically effective amount. The term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level may be determined according to factors including the health condition of a patient, type and severity of disease, activity of drug, sensitivity to drug, administration method, administration time, administration route and excretion rate, treatment period, drugs combined or used concurrently, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by those skilled in the art. The daily dose of the composition of the present invention is about 0.01 mg / kg to 1000 mg / kg, preferably 0.1 mg / kg to 100 mg / kg, and may be administered once a day to several times a day in divided doses. The term “administration” of the present invention means introducing a predetermined substance into a patient by an appropriate method, and the route of administration of the composition may be any general route as long as the composition can reach the target tissue. In addition, the pharmaceutical composition of the present invention may also be administered by any device through which the active substance can move to the target tissue. For example, the pharmaceutical composition may be administered by transdermal administration, oral administration, intrathecal administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, inner ear administration, intrauterine dural administration, sublingual administration, or intracerebrovascular injection, but is not limited thereto. In the present invention, the pharmaceutical composition may appropriately comprise, if necessary, depending on the administration method or formulation, a suspending agent, solubilizer, stabilizer, isotonic agent, preservative, adsorption inhibitor, surfactant, diluent, excipient, pH-adjusting agent, soothing agent, buffer, reducing agent, antioxidant, etc. Pharmaceutically acceptable carriers and formulations suitable for the present invention, including those exemplified above, are described in detail in [Remington's Pharmaceutical Sciences, 19th ed., 1995]. The pharmaceutical composition may be prepared in a unit dosage form by formulation using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention belongs, or may be prepared by being placed in a multi-dose container. In particular, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of a powder, granule, tablet, or capsule. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid formulations are formulated by mixing the composition with at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition, lubricants such as magnesium stearate and talc may be used in addition to simple excipients. Examples of liquid formulations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc., may be included in addition to water and liquid paraffin, which are commonly used simple diluents. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used. As bases for suppositories, Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc. may be used. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, preservatives, etc. The route of administration of the pharmaceutical composition of the present invention may be any general route as long as it can reach the target tissue, but the pharmaceutical composition may be administered through subcutaneous injection using an osmotic pump, intradermal injection, intravenous injection, intraperitoneal injection, intravitreal injection, oral administration, etc. The term “prevention” used in the present invention means all acts of suppressing a disease or delaying the onset thereof by administration of the composition. In the present invention, “treatment” means all acts of improving or beneficially changing symptoms of a disease by administration of the composition. The term “subject” of the present invention means any animal in which a disease has occurred or may occur, and typically may be an animal that is capable of exhibiting a beneficial effect by treatment using the composition of the present invention, but includes, without limitation, any subject that has symptoms of a disease or is likely to have such symptoms. As described above, a disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with an existing disease therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. In addition, still another aspect of the present invention provides a treatment method comprising administering the pharmaceutical composition. In addition, still another aspect of the present invention provides a cosmetic composition comprising the composition for delivering a functional substance. In the present invention, the composition may be formulated in various forms by adding various components as auxiliary components for delivery, stabilization, etc. In the present invention, the cosmetic composition may have a formulation such as a mist, serum, nourishing skin lotion, softening skin lotion, softening water, emulsion, suspension, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, moisture cream, hand cream, foundation, powder, makeup base, essence, nourishing essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, facial cleanser, treatment, beauty solution, beauty pack, ointment, gel, liniment, solution, patch, spray, bath preparation, sunscreen, sun oil, and hair product. The scope of the formulation is not limited thereto, and the formulation of the cosmetic composition may be manufactured into any formulation commonly manufactured in the art. In the present invention, the cosmetic composition may further comprise a cosmetically acceptable carrier. The type of the cosmetically acceptable carrier of the present invention is not particularly limited as long as it does not inhibit the activity and characteristics of the cosmetic composition of the present invention, and any cosmetically acceptable carrier commonly used in the technical field may be used. Non-limiting examples of the cosmetically acceptable carrier include saline, sterile water, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, etc. These may be used alone or in a combination of two or more thereof. In the present invention, the cosmetically acceptable carrier varies depending on the formulation of the cosmetic composition. When the formulation is a paste, cream, or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, or the like may be used as a carrier component. When the formulation is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, and particularly in the case of a spray, a propellant such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether may be additionally included. When the formulation is a solution or emulsion, a solvent, solubilizer, or emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol oil, glycerol fatty acid ester, polyethylene glycol, or sorbitan fatty acid ester. When the formulation is a suspension, liquid diluents such as water, ethanol, or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or the like may be used as a carrier component. When the formulation of the cosmetic composition is a soap, alkali metal salts of fatty acids, fatty acid hemiester salts, fatty acid protein hydrolysates, isethionate, lanolin derivatives, aliphatic alcohols, vegetable oils, glycerol, sugars, or the like may be used as a carrier component, but the carrier component is not limited thereto. When the formulation of the cosmetic composition is a pack, it includes all forms of a peel-off pack containing polyvinyl alcohol or the like, a wash-off pack in which a pigment such as kaolin, talc, zinc oxide, or titanium dioxide is contained in a general emulsion-type cosmetic, or a mask sheet pack, and is not particularly limited thereto. The components included in the cosmetic composition may include components commonly used in cosmetic compositions in addition to the composition for delivering a functional substance as an active ingredient, and may include, for example, conventional auxiliary agents and carriers such as stabilizers, solubilizers, preservatives, moisturizers, pigments, sterilizers, antioxidants, surfactant vitamins, and fragrances. In addition, the cosmetic composition may further comprise a skin absorption enhancer in order to enhance the effect thereof. In the present invention, the composition may further comprise one or more active ingredients exhibiting the same or similar efficacy. In the present invention, the composition for delivering a functional substance may be included in an amount of 0.000000001 wt% to 90 wt%, for example, 0.000000001 wt% to 80 wt%, 0.000000001 wt% to 60 wt%, 0.000000001 wt% to 30 wt%, 0.000000001 wt% to 20 wt%, 0.000000001 wt% to 10 wt%, 0.000000001 wt% to 5 wt%, 0.000000001 wt% to 0.001 wt%, 0.000000001 wt% to 0.0001 wt%, 0.000000001 wt% to 0.00001 wt%, 0.0001 wt% to 90 wt%, 0.0001 wt% to 80 wt%, 0.0001 wt% to 60 wt%, 0.0001 wt% to 30 wt%, 0.0001 wt% to 20 wt%, 0.0001 wt% to 10 wt%, 0.0001 wt% to 5 wt%, 0.001 wt% to 90 wt%, 0.001 wt% to 80 wt%, 0.001 wt% to 60 wt%, 0.001 wt% to 30 wt%, 0.001 wt% to 20 wt%, 0.001 wt% to 10 wt%, 0.001 wt% to 5 wt%, 0.01 wt% to 90 wt%, 0.01 wt% to 80 wt%, 0.01 wt% to 60 wt%, 0.01 wt% to 30 wt%, 0.01 wt% to 20 wt%, 0.01 wt% to 10 wt%, 0.01 wt% to 5 wt%, 0.1 wt% to 90 wt%, 0.1 wt% to 80 wt%, 0.1 wt% to 60 wt%, 0.1 wt% to 30 wt%, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, or 0.1 wt% to 5 wt%, based on the total weight of the cosmetic composition. When included in an amount of less than 0.000000001 wt%, skin improvement effects, etc. are insignificant, and when included in an amount of more than 90.0 wt%, efficiency relative to the amount of material input decreases, and thus it is not economical. In one specific embodiment, the cosmetic composition may include the composition for delivering a functional substance at a concentration of 105 particles / mL to 1010 particles / mL, for example, 105 particles / mL to 109 particles / mL, 105 particles / mL to 108 particles / mL, 105 particles / mL to 107 particles / mL, 105 particles / mL to 106 particles / mL, 106 particles / mL to 1010 particles / mL, 106 particles / mL to 109 particles / mL, 106 particles / mL to 108 particles / mL, 106 particles / mL to 107 particles / mL, 107 particles / mL to 1010 particles / mL, 107 particles / mL to 109 particles / mL, 107 particles / mL to 108 particles / mL, 108 particles / mL to 1010 particles / mL, 108 particles / mL to 109 particles / mL, or 109 particles / mL to 1010 particles / mL. In addition, still another aspect of the present invention provides a method for preparing a composition for delivering a functional substance, comprising the following steps. (a) centrifuging a supernatant obtained by culturing cells; (b) filtering and then purifying the supernatant obtained by the centrifugation; (c) centrifuging the purified supernatant several times. For example, the centrifugation of step (c) may be primarily performed at 5,000 g to 15,000 g, through which large extracellular vesicles or small extracellular particles may be obtained. For example, after the primary performance, secondary centrifugation may be performed at 100,000 g to 200,000 g, through which small extracellular vesicles or non-vesicular extracellular particles may be obtained. For example, after the secondary centrifugation, tertiary centrifugation may be performed at 150,000 g to 200,000 g, through which exomeres may be obtained. For example, after the tertiary centrifugation, quaternary centrifugation may be performed at 350,000 g to 400,000 g, through which supermeres may be obtained. In one embodiment of the present invention, the cells of step (a) may be cells into which a functional substance, for example, a gene, has been introduced, but are not limited thereto. In one embodiment of the present invention, the method for preparing a composition for delivering a functional substance may further comprise mixing with a functional substance to be delivered, for example, a gene,.through the obtained supermeres. In addition, still another aspect of the present invention provides a method for delivering a functional substance to cells by a non-vesicular extracellular particle (NVEP). The non-vesicular extracellular particle and the functional substance are as described above. In addition, still another aspect of the present invention provides a kit for delivering a functional substance, comprising a non-vesicular extracellular particle (NVEP) as an active ingredient. The non-vesicular extracellular particle, functional substance, and delivering a functional substance are as described above. The carrier means is suitable for containing one or more containers, such as bottles and tubes, and each container contains independent components used in the method of the present invention. In addition, the kit may include instructions. The instructions are printed matter that describes how to use the kit, for example, the presented reaction conditions, etc. The instructions include an instruction booklet in the form of a pamphlet or leaflet, a label attached to the kit, and a description on the surface of a package comprising the kit. In addition, the instructions include information disclosed or provided through an electronic medium such as the Internet. Still another aspect of the present invention provides a kit for delivering a functional substance, comprising a non-vesicular extracellular particle marker protein; and a non-vesicular extracellular particle (NVEP) comprising a functional substance of interest. The non-vesicular extracellular particle marker protein may be a nonspecific protein, but is not limited thereto. For example, the nonspecific protein may be a protein present in the non-vesicular extracellular particle, or may be a protein that exists outside the non-vesicular extracellular particle and moves to the non-vesicular extracellular particle when overexpressed in cells, but is not limited thereto. The non-vesicular extracellular particle, non-vesicular extracellular particle marker protein, functional substance of interest, delivering a functional substance, and kit are as described above. Still another aspect of the present invention provides a composition for delivering a functional substance, comprising a non-vesicular extracellular particle marker protein and a functional substance of interest. The non-vesicular extracellular particle, non-vesicular extracellular particle marker protein, functional substance of interest, and delivering a functional substance are as described above. In addition, still another aspect of the present invention provides a method for delivering a functional substance by the composition for delivering a functional substance. In addition, still another aspect of the present invention provides a use of a composition for delivering a functional substance comprising a non-vesicular extracellular particle for delivering a functional substance. In addition, still another aspect of the present invention provides a use of a non-vesicular extracellular particle for delivering a functional substance. [Mode For Carrying Out the Invention] Hereinafter, the present invention will be described in more detail through examples. These examples are provided to more specifically describe the present invention, and the scope of the present invention is not limited by these examples. Example 1: Method for collecting subclassified substances of extracellular particles Extracellular particles including supermeres, exomeres, and small extracellular vesicles were isolated and obtained from HEK293FT cell lines and human bone marrow-derived stem cells (FIG. 2). Specifically, donor cells were seeded in a 150 n culture dish at 4.5 x 106 cells, and 20 mL of cell culture medium (DMEM high glucose + FBS 10% + AA 1%) was added and cultured for 48 hours. Thereafter, the supernatant was removed and washed once with DPBS, and then replaced with 19 mL of serum-free medium (DMEM high glucose + AA 1% + Glutamax 1%) and pre-cultured for 30 minutes. When transduction was required, pcDNA3.1 and PEI were mixed in serum-free medium to prepare a transduction reagent, reacted at room temperature for 15 minutes, and then added to donor cells. Six hours after the transduction, the medium was replaced with serum-free medium, and 48 hours later, the final supernatant was obtained. Extracellular particles obtained without transduction were also collected in the same manner. The obtained supernatant was centrifuged at 3000 g for 5 minutes and filtered through a 0.45 pm filter (Sartolab RF500 PES). Thereafter, concentration was performed using concentration Amicon (10 kDa filter, UFC901024, Merck) or TFF (100 kDa, S04-E100-05-N, Repligen). Then, the supernatant was centrifuged at 10,000 g for 30 minutes and further ultracentrifuged at 150,000 g for 90 minutes under 4°C conditions (Ultracentrifuge, Beckman). Small extracellular vesicles were separated using 1X PBS-PIC (storage on ice for at least 20 minutes, followed by centrifugation at 13,000 g for 20 minutes), and the supernatant of the small extracellular vesicles was transferred to a UC tube (355655) and centrifuged at 167,000 g for 16 hours. After exomeres were separated using 1X PBS-PIC (storage on ice for at least 20 minutes, followed by centrifugation at 13,000 g for 20 minutes), the exomere supernatant was transferred to a 70Ti rotor high speed tube (355618) and ultracentrifuged at 367,000 g for 16 hours. Supermeres were separated from the pellet generated after ultracentrifugation using 1X PBS-PIC (storage on ice for at least 20 minutes, followed by short centrifugation for 2 minutes). Example 2: Confirmation of marker expression using supermeres Supermeres were isolated from the HEK293FT cell line according to the collection method described in Example 1, and the marker expression pattern thereof was compared with those of exomeres and small extracellular vesicles. Automated Western blotting (ProteinSimple) was performed on the isolated small extracellular vesicles, exomeres, and supermeres. TGFBI (10188-1-AP-20UL), enolase-1 (3810T), enolase-2 (8171S), HSPA13 (sc-398297), and CD81 (EXOAB- CD81A1) antibodies were each used after being diluted 1:100, and 3 pg of each substance was loaded to confirm protein expression. As a result, the HEK293FT-derived supermeres exhibited a protein expression pattern distinguished from those of exomeres and small extracellular vesicles (FIG. 3). From these results, it was confirmed that supermeres can be detected using TGFBI, ENO1, ENO2, HSPA13, and CD81 as markers. Example 3. Confirmation of cell delivery of functional substance loaded inside extracellular particles (EPs) An experiment was performed to confirm whether a functional substance transduced into donor cells is loaded inside extracellular particles and delivered to recipient cells. This experiment was confirmed according to the process reported at https: / / doi.org / 10.1016 / j.cell.2023.06.013. HEK293FT cells were used as donor cells and recipient cells, and extracellular particles were isolated and obtained according to the collection method described in Example 1. For transduction, HEK293FT cells were treated with a transduction reagent (1 mL) in which pcDNA3.1-eGFP-MS2X2 (60 pg) and PEI (240 pg) were mixed, and 6 hours later, the medium was replaced with serum-free medium, and 48 hours later, the supernatant was obtained. The plasmid used was prepared by cloning a polynucleotide (SEQ ID NO: 2) encoding the eGFP-MS2X2 protein (SEQ ID NO: 1) into a pcDNA3.1 vector (ThermoFisher). Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium 500 pL). After 24 hours, the supernatant was aspirated and washed once with DPBS. Extracellular particles were thoroughly mixed in serum-free medium to a final volume of 500 pL and incubated for 48 hours. In addition, a group separately treated with RNase A was additionally prepared in the same process. The group treated with RNase A was used by incubating extracellular particles at 37°C for 30 minutes and then treating the same with RNase A at 1 pg / mL. After 48 hours, attached recipient cells were collected with a cell scraper (90020), and automated Western blotting (ProteinSimple) was performed. As a result, as confirmed in FIG. 4, when eGFP was overexpressed in cells and then extracellular particles were isolated and treated by concentration, it was confirmed that eGFP expression increased in recipient cells 48 hours later, when all proteins were removed. In addition, it was confirmed that there was no difference in eGFP expression in recipient cells even when extracellular particles and RNase A were treated together. These results suggest that the eGFP functional substance loaded in extracellular particles by an endogenous loading method can be delivered to recipient cells through the extracellular particles, and that the loaded functional substance is stably maintained despite RNase A treatment. Example 4. Confirmation of cell delivery of a functional substance loaded inside small extracellular particles An experiment was performed to confirm in which type of particles among extracellular particles the eGFP-MS2X2 functional substance delivered from donor cells to recipient cells was loaded. This experiment was confirmed according to the process reported at https: / / doi.org / 10.1016 / j.cell.2023.06.013. HEK293FT cells were used as donor cells and recipient cells. The donor cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1-eGFP-MS2X2 60 pg + PEI 240 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1. Small extracellular particles were isolated and obtained from the 10,000 g centrifugation supernatant, and large extracellular vesicles were isolated and obtained from the 18,000 g centrifugation pellet. Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium 500 pL), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Thereafter, extracellular particles, small extracellular particles, and large extracellular vesicles were each mixed in serum-free medium, and a final 500 pL obtained therefrom was incubated for 24 hours. After incubation, attached recipient cells were collected with a cell scraper (90020), and automated Western blotting (ProteinSimple) was performed. As a result, as confirmed in FIG. 5, when eGFP-MS2X2 mRNA was overexpressed in cells and then extracellular particles (EPs), small extracellular particles (small EPs), and large extracellular vesicles (Large EVs) were isolated and treated by concentration, it was confirmed that eGFP expression in recipient cells after 24 hours increased more by small extracellular particles than by the total extracellular particle population. On the other hand, it was confirmed that eGFP was not expressed in cells treated with large extracellular vesicles having a micro size. These results suggest that the eGFP-MS2X2 functional substance overexpressed in cells can be delivered to recipient cells more effectively by extracellular particles other than large extracellular vesicles. Example 5. Confirmation of cell delivery of functional substance loaded inside non-vesicular extracellular particles (NVEPs) An experiment was performed to confirm in which particles among those included in small extracellular particles (small EPs) the eGFP-MS2X2 functional substance delivered from donor cells to recipient cells was loaded. HEK293FT cells were used as donor cells and recipient cells. Donor cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1-eGFP-MS2X2 60 pg + PEI 240 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular particles were isolated and obtained from the 10,000 g centrifugation supernatant, large extracellular vesicles were isolated and obtained from the 18,000 g centrifugation pellet, and non-vesicular extracellular particles and small extracellular vesicles were respectively isolated and obtained from the 150,000 g ultracentrifugation supernatant and pellet. Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium 500 pL), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Thereafter, extracellular particles, large extracellular vesicles, small extracellular particles, small extracellular vesicles, and non-vesicular extracellular particles were each mixed in serum-free medium, and a final 500 pL obtained therefrom was incubated for 48 hours. After incubation, attached recipient cells were collected with a cell scraper (90020), and automated Western blotting (JESS Protein Simple) was performed. As a result, as shown in FIG. 6, when eGFP-MS2X2 mRNA was overexpressed in cells and then extracellular particles, large extracellular vesicles, small extracellular particles, small extracellular vesicles, and non-vesicular extracellular particles were isolated and treated, it was confirmed that eGFP expression in recipient cells was in the order of non-vesicular extracellular particles > small extracellular particles > extracellular particles > small extracellular vesicles > large extracellular vesicles. In addition, in order to exclude the influence according to the difference in plasmid sequence, after an eGFP plasmid without MS2X2 was transduced under the same conditions as the pcDNA3.1-eGFP-MS2X2, extracellular particles such as non-vesicular extracellular particles and small extracellular vesicles were each isolated and treated to recipient cells. To prepare the pcDNA3.1-eGFP plasmid, a polynucleotide (SEQ ID NO: 4) encoding the eGFP protein (SEQ ID NO: 3) was cloned into the pcDNA3.1 vector and used. As a result of the experiment, it was confirmed that, also in the case of the eGFP plasmid, eGFP expression was highest in recipient cells treated with non-vesicular extracellular particles compared with other particles, as in eGFP-MS2X2 (FIG. 7). These results suggest that, regardless of the sequence type of a plasmid overexpressed in cells, the overexpressed functional substance (protein and mRNA) is mainly loaded into non-vesicular extracellular particles having a size of 50 nm or less and effectively delivered to recipient cells. Example 6: Confirmation of cell delivery of functional substance loaded inside supermeres It was confirmed whether a functional substance transduced into donor cells was loaded into and delivered by supermeres among non-vesicular extracellular particles. HEK293FT cells were used as donor cells and recipient cells. Donor cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1-eGFP-MS2X2 or pcDNA3.1-myc MCP 30 pg + PEI 120 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. In particular, the pcDNA3.1-eGFP-MS2X2 plasmid was the same as that prepared in Example 2, and in order to prepare the pcDNA3.1-myc MCP plasmid, a polynucleotide encoding the myc-MCP protein (SEQ ID NO: 5) was cloned into the pcDNA3.1 vector. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular particles were isolated and obtained from the 10,000 g centrifugation supernatant, large extracellular vesicles were isolated and obtained from the 18,000 g centrifugation pellet, non-vesicular extracellular particles and small extracellular vesicles were respectively isolated and obtained from the 150,000 g ultracentrifugation supernatant and pellet, and supermeres and exomeres were respectively isolated and obtained from the 167,000 g ultracentrifugation supernatant and pellet. Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium 500 pL), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Thereafter, each nanoparticle was thoroughly mixed in serum-free medium by adjusting the concentration based on protein for each group, and a final 500 pL obtained therefrom was incubated for 48 hours. After incubation, attached recipient cells were collected with a cell scraper (90020), and automated Western blotting (ProteinSimple) was performed. As a result, using two types of functional substances, eGFP-MS2 and myc-MCP, it was confirmed that, among non-vesicular extracellular particles, supermeres perform a role of mainly delivering the loaded functional substances to recipient cells (FIG. 8). Example 7: Confirmation of intracellular endogenous drug delivery ability of supermeres Example 7-1. Analysis of contents of mRNA and protein, which are functional substances, in supermeres, exomeres, and small extracellular vesicles An experiment was performed to compare the intracellular drug delivery abilities of supermeres, exomeres, and small extracellular vesicles. First, the amounts of mRNA contained in each extracellular particle isolated from cells transduced with an eGFP plasmid were comparatively analyzed. Specifically, HEK293FT cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1-eGFP 60 pg + PEI 240 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular particles were isolated and obtained from the 10,000 g centrifugation supernatant, small extracellular vesicles were isolated and obtained from the 150,000 g ultracentrifugation pellet, exomeres were isolated and obtained from the 167,000 g ultracentrifugation pellet, and supermeres were isolated and obtained from the 367,000 g pellet. Total RNA was extracted from supermeres, exomeres, and small extracellular vesicles using a miRNeasy Mini Kit (271004, Qiagen) according to the manufacturer's protocol. The extracted RNA was synthesized into cDNA using TOPscriptTM (EZ005S, Enzynomics). eGFP IVT mRNA (Genscript) was set as a standard, and the amount of eGFP mRNA in each substance was quantified through RT-qPCR absolute quantification. In addition, automated Western blotting (ProteinSimple) was performed on the isolated supermeres, exomeres, and small extracellular vesicles. An eGFP antibody (1:100, CAB4211, Invitrogen) was used, and 3 pg each of the supermeres, exomeres, and small extracellular vesicles was loaded. As a result, it was confirmed that the amount of eGFP mRNA in small extracellular vesicles was 80 times that in supermeres, and that the amount of eGFP mRNA in exomeres was 30 times that in supermeres (FIG. 9). Protein amount analysis further confirmed that the amount of eGFP protein in small extracellular vesicles was 1.25 times that in supermeres, and that the amount of eGFP protein in exomeres was 1.85 times that in supermeres (FIG. 10). Example 7-2. Comparison of endogenous functional substance delivery abilities of supermeres, exomeres, and small extracellular vesicles An experiment was performed to compare the endogenous functional substance delivery abilities of the supermeres, exomeres, and small extracellular vesicles obtained in Example 7-1. Specifically, HEK293FT cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1-eGFP 60 pg + PEI 240 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular vesicles were isolated and obtained from the 150,000 g ultracentrifugation pellet, exomeres were isolated and obtained from the 167,000 g ultracentrifugation pellet, and supermeres were isolated and obtained from the 367,000 g pellet. Total RNA was extracted from supermeres, exomeres, and small extracellular vesicles using a miRNeasy Mini Kit (271004, Qiagen) according to the manufacturer's protocol. The extracted RNA was synthesized into cDNA using TOPscriptTM (EZ005S, Enzynomics). The eGFP plasmid was set as a standard, and the amount of eGFP mRNA in each substance was quantified through RT-qPCR absolute quantification. Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium 500 pL), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Each sample was mixed in serum-free medium to prepare a final volume of 500 pL, and incubation was performed for 48 hours. Thereafter, 1X RIPA + PIC 100 pL was added, and attached recipient cells were collected with a cell scraper (90020). The obtained cell lysate was vortexed 4 times every 5 minutes and then centrifuged at 16,000 g for 20 minutes. After obtaining the supernatant, automated Western blotting (ProteinSimple) was performed. Protein expression was confirmed by loading 3 pg of the cell lysate using eGFP (1:100, CAB4211). As a result, it was confirmed that supermeres exhibited up to 20-fold higher mRNA delivery efficiency in recipient cells than small extracellular vesicles and exomeres (FIG. 11), and that, in the case of small extracellular vesicles and exomeres, eGFP protein expression was not induced in recipient cells, but supermeres induced eGFP protein expression in recipient cells (FIG. 12). These results suggest that, although supermeres contain smaller amounts of eGFP protein and mRNA than small extracellular vesicles or exomeres, supermeres have an excellent ability to efficiently deliver endogenous functional substances through outstanding delivery efficiency and maximize functional drug delivery. Example 8: Confirmation of intracellular internalization of supermeres through lipid raft pathway Since identifying the internalization route of supermeres provides important clues for the characteristics of supermeres, maximization of gene delivery efficiency, and development of new applications, an experiment was performed to confirm the intracellular internalization route of supermeres. Specifically, HEK293FT cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1 30 pg + PEI 120 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular vesicles were isolated and obtained from the 150,000 g ultracentrifugation pellet, exomeres were isolated and obtained from the 167,000 g ultracentrifugation pellet, and supermeres were isolated and obtained from the 367,000 g pellet. To stain the obtained supermeres, Cy5.5-NHS ester (Lumiprobe) was mixed at a ratio of 1 mg / mL : 1 pg / mL and pipetted, and incubated overnight at 4°C to induce a fluorescence-supermere reaction. Unbound fluorescent dye was removed using a ZebaTM Spin Desalting column (40K MWCO, Thermo Fisher Scientific). HEK293FT cells, which are recipient cells, were seeded in a 24-well plate containing serum-free medium (500 pL) at 2.5 x 105 cells / well and incubated at 37°C for 24 hours. Three inhibitors, chlorpromazine (CPZ, clathrin-mediated endocytosis inhibitor) 10 pM, 5-(N-ethyl-N-isopropyl)-amiloride (EIPA , macropinocytosis inhibitor) 50 pM, and methyl-P-cyclodextrin ( M0CD, lipid raft-mediated endocytosis inhibitor) 10 mM, were each treated and then incubated at 37°C for 30 minutes. After washing the cells with DPBS, the medium was replaced with serum-free DMEM. Each well was treated with Cy5.5-labeled supermeres 50 pg / mL and incubated, and the relative MFI of each Cy5.5 was measured at 30 minutes, 3 hours, and 24 hours. In addition, to confirm Cy5.5 expression in recipient cells, the cells were washed once with cold DPBS (Ca2+ and Mg2+-free, Welgene), detached using Trypsin-EDTA, and then centrifuged at 300 g for 3 minutes to pellet the cells. The pelleted cells were resuspended in 200 pL of DPBS, and Cy5.5 expression in single cells was confirmed through flow cytometry. As a result, supermere uptake decreased upon treatment with CPZ, EIPA, and MPCD, and, in particular, supermere uptake decreased most greatly upon treatment with MPCD, thereby confirming that supermeres are mainly internalized into cells through lipid rafts (FIG. 13). FIGS. 13a and 13b show results confirming Cy5.5 expression in recipient cells at 30 minutes, 3 hours, and 24 hours after treating the recipient cells with each drug and supermeres. FIG. 13c shows changes in the ratio of cells containing supermeres stained with Cy5.5 for 24 hours after treating recipient cells with each drug and supermeres. Example 9: Confirmation of intracellular exogenous drug delivery ability of supermeres In the field of mRNA-based therapeutics, studies on a method of exogenously loading externally synthesized mRNA into a carrier have attracted attention, and thus the possibility of delivery of mRNA exogenously loaded into supermeres was evaluated. Specifically, HEK293FT cells were treated with 1 mL of a transduction reagent prepared by mixing pcDNA3.1 30 pg + PEI 120 pg in serum-free medium, and after 6 hours, the medium was replaced with serum-free medium, and after 48 hours, the supernatant was obtained. The obtained supernatant was pretreated and concentrated according to the collection method described in Example 1, and small extracellular vesicles were isolated and obtained from the 150,000 g ultracentrifugation pellet, exomeres were isolated and obtained from the 167,000 g ultracentrifugation pellet, and supermeres were isolated and obtained from the 367,000 g pellet. For treatment of recipient cells, cells were seeded in a 24-well plate at 2.8 x 105 cells / well (cell culture medium), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Thereafter, experiments were performed by dividing small extracellular vesicles, exomeres, and supermeres into groups as shown in Table 1 below. [Table 1] Classification Group name Dose eGFP mRNA added Free mRNA Free mRNA - 6 pg / mL Small extracellular vesicles Dose 1 6 pg(12 pg / mL) 0.75 pg(1.5 pg / mL) Dose 2 12 pg(24 pg / mL) 1.5 pg(3 pg / mL) Dose 3 24 pg(48 pg / mL) 3 pg(6 pg / mL) Exomeres Dose 1 6 pg(12 pg / mL) 0.75 pg(1.5 pg / mL) Dose 2 12 pg(24 pg / mL) 1.5 pg(3 pg / mL) Dose 3 24 pg(48 pg / mL) 3 pg(6 pg / mL) Supermeres Dose 1 30 pg(60 pg / mL) 1 pg(2 pg / mL) Samples were mixed according to the conditions for each group and incubated at room temperature for 15 minutes. Each group was mixed in serum-free medium to prepare a final volume of 500 pL, and incubation was performed for 48 hours. Thereafter, 1X RIPA + PIC 100 pL was added, and attached recipient cells were collected with a cell scraper (90020). The obtained cell lysate was vortexed 4 times every 5 minutes and 33 then centrifuged at 16,000 g for 20 minutes, and after obtaining the supernatant, automated Western blotting (ProteinSimple) was performed. Protein expression of each group was confirmed by loading 3 pg of each cell lysate using eGFP (1:100, CAB4211, Invitrogen) and beta-actin (1:500, MAB8929, R&D Systems) antibodies. As a result, when mRNA was delivered into cells using small extracellular vesicles and exomeres as carriers, protein expression was not confirmed, thereby confirming that delivery did not occur. On the other hand, in the case of supermeres, expression of the target protein was confirmed, and it was confirmed that intracellular delivery of mRNA through supermeres was possible (FIG. 14). Example 10: Confirmation of intracellular exogenous pDNA delivery ability of supermeres An experiment was performed to confirm whether supermeres are capable of delivering not only mRNA but also exogenously loaded pDNA. Supermeres were isolated and obtained according to the collection method described in Example 1. Thereafter, HEK293FT cells, which are recipient cells, were seeded in a 6-well or 24-well plate at 2.8 x 105 cells / well (medium 500 pL: DMEM, high glucose + FBS 10% + AA 1%), and after 24 hours, the supernatant was aspirated and washed once with DPBS. Thereafter, groups under the conditions shown in Table 2 below were respectively prepared. [Table 2] Group (6 well) Plasmid Supermeres PEI Non-treated None None None Free DNA eGFP 3 pg (1.5 pg / mL) None None Positive None 12 pg Dose 1 6 pg(3 pg / mL) None Dose 2 12 pg(6 pg / mL) None Dose 3 24 pg(12 pg / mL) None Group (24 well) Plasmid Supermeres Non-treated None None Dose 1 eGFP pDNA 0.375 pg(0.375 pg / mL) 3 pg(6 pg / mL) Dose 2 eGFP pDNA 0.75 pg(1.5 pg / mL) 6 pg(12 pg / mL) Dose 3 eGFP pDNA 1.5 pg(3 pg / mL) 12 pg(24 pg / mL) Each prepared group was incubated at room temperature for 15 minutes, mixed in the medium to prepare a final volume of 500 pL, and then incubated for 48 hours. Thereafter, 1X RIPA + PIC 100 pL was added, attached recipient cells were collected with a cell scraper (90020), and the obtained cell lysate was vortexed every 5 minutes and repeated 4 times, followed by centrifugation at 16,000 g for 20 minutes. Automated Western blotting (ProteinSimple) was performed with the obtained supernatant. As a result, expression of pDNA, which is the target protein, was confirmed in recipient cells, and it was confirmed that intracellular delivery of pDNA through supermeres was possible (FIG. 15). Example 11: Comparison of gene delivery abilities of supermeres and lipid nanoparticles An experiment was performed to verify in vivo the exogenous mRNA delivery ability of supermeres confirmed at the cellular level and, at the same time, to compare gene delivery ability with lipid nanoparticles (LNPs), which are widely used as mRNA carriers. Specifically, small extracellular vesicles and supermeres were isolated and obtained from HEK293FT cells according to the collection method described in Example 1. Thereafter, C57BL / 6, male, 7-week-old mice were prepared and fed alfalfa-free feed, samples as shown in Table 3 below were prepared, and fasting was performed one day before sample injection. [Table 3] Classification Dose Amount of eGFP mRNA added Free mRNA - 20 pg Lipid 20 pg 1 pg nanoparticles 200 pg 10 pg Supermeres 8 pg 1 pg 80 pg 10 pg 160 pg 20 pg Each group of Table 3 was intravascularly injected into mice, and after 18 hours, the mice were sacrificed and organs were extracted. The extracted organs were measured using an IVIS spectrum (Caliper Life Sciences, IVIS® Lumina Series III) to measure fluorescence values of the target protein translated in vivo. As a result, it was confirmed that supermeres exhibited a stronger GFP fluorescence signal in the intestine compared to LNPs (FIG. 16), and delivered mRNA better, thereby exhibiting stronger protein expression (FIG. 17). Example 12: Analysis of accumulation of supermeres in organs Example 12-1. Comparison of in vivo accumulation of HEK293FT cell-derived supermeres and small extracellular vesicles Since lipid nanoparticles mainly used as mRNA carriers have a problem in that a significant number thereof accumulate in the liver and spleen and cannot be systematically distributed in vivo, an in vivo distribution experiment was performed to confirm whether supermeres also have such side effects. Specifically, small extracellular vesicles and supermeres were isolated from HEK293FT cells according to the collection method described in Example 1, and small extracellular vesicles and supermeres were each mixed with sulfo-Cyanine5.5 NHS ester (Cy5.5; Lumiprobe, 17320) at a ratio of 1 pg of Cy5.5 per 100 pg of particles and incubated overnight at 4°C. Unbound Cy5.5 was removed using ZebaTM Spin Desalting Columns (A57761), and fluorescence values between samples were unified using a microplate reader. Thereafter, C57BL / 6, male, 7-week-old mice were fed alfalfa-free feed and fasted the day before sample injection. Free dye (200 pL), Cy5.5-labeled small extracellular vesicles (200 pg), or Cy5.5-labeled supermeres (200 pg) were intravascularly injected, and after 18 hours, the mice were sacrificed and organs were extracted. The extracted organs were measured using an IVIS spectrum (Caliper Life Sciences, IVIS® Lumina Series III) to measure Cy5.5 fluorescence values remaining in the organs. As a result, it was confirmed that supermeres accumulated relatively less in the liver and spleen and accumulated well in the kidney compared to small extracellular vesicles (FIGS. 18 and 19). Example 12-2. Comparison of in vivo accumulation of stem cell-derived supermeres and small extracellular vesicles In order to confirm that supermeres derived from various cells as well as HEK293FT cells can be used as drug carriers, small extracellular vesicles, exomeres, and supermeres derived from human bone marrow stem cells were secured, and in vivo accumulation was confirmed. Specifically, small extracellular vesicles, exomeres, and supermeres were isolated from human bone marrow stem cells according to the collection method described in Example 1, and small extracellular vesicles, exomeres, and supermeres were each mixed with sulfo-Cyanine5.5 NHS ester (Cy5.5; Lumiprobe, 17320) at a ratio of 1 pg of Cy5.5 per 100 pg of particles and incubated overnight at 4°C. Unbound Cy5.5 was removed using ZebaTM Spin Desalting Columns (A57761), and fluorescence values between samples were unified using a microplate reader. Thereafter, C57BL / 6, male, 7-week-old mice were fed alfalfa-free feed and fasted the day before sample injection. Free dye (100 pL), Cy5.5-labeled small extracellular vesicles (100 pL), Cy5.5-labeled exomeres (100 pg), or Cy5.5-labeled supermeres (100 pg) were intravascularly injected, and after 6 hours had elapsed after injection, the mice were sacrificed and organs (brain, heart, lung, liver, kidney, spleen, intestine, and bladder) were extracted. The extracted organs were measured using an IVIS spectrum (Caliper Life Sciences, IVIS® Lumina Series III) to measure Cy5.5 fluorescence values remaining in the organs. As a result, as in HEK293FT, it was confirmed that supermeres derived from human bone marrow stem cells accumulated significantly less in the liver and spleen and accumulated well in the kidney compared to small extracellular vesicles (FIG. 20). Example 13: Confirmation of selective loading of substance of interest inside supermeres through supermere marker-functional substance fusion It was experimentally confirmed that a functional substance of interest can be specifically loaded into supermeres by fusing a marker and a functional protein of interest to supermeres and expressing the same in supermeres. Supermeres were isolated and obtained from HEK293FT cells according to the collection method described in Example 1. For transduction, HEK293FT cells were treated with a transduction reagent (1 mL) prepared by respectively mixing pcDNA3.1-TGFBI-Myc (60 pg), pcDNA3.1-T7-TGFBI-Myc (60 pg), and PEI (240 pg), and 6 hours later, the medium was replaced with serum-free medium, and 48 hours later, the supernatant was obtained. The plasmids used were prepared by cloning a polynucleotide encoding the TGFBI-Myc protein (SEQ ID NO: 6) into a pcDNA3.1 vector (ThermoFisher), and a polynucleotide encoding the T7-TGFBI-Myc protein (SEQ ID NO: 7) into a pcDNA3.1 vector (ThermoFisher). Six hours after transduction, the medium was replaced with serum-free medium, and 48 hours later, the final supernatant was obtained.  The cell supernatant was centrifuged at 3000 g for 5 minutes and filtered through a 0.45 pm filter (Sartolab RF500 PES).   After concentration with Amicon (10 kDa filter, UFC901024, Merck), the supernatant was centrifuged at 10,000 g for 30 minutes. Thereafter, the supernatant was further ultracentrifuged at 150,000 g for 90 minutes at 4°C (Ultracentrifuge, Beckman), and the supernatant was transferred to a UC tube (355655) and centrifuged at 167,000 g for 16 hours. Thereafter, the supernatant was further transferred to a 70Ti rotor high speed tube (355618) and centrifuged at 367,000 g for 16 hours. Thereafter, supermeres were separated from the generated pellet using 1X PBS-PIC (storage on ice for at least 20 minutes, followed by short centrifugation for 2 minutes). Automated Western blotting (ProteinSimple) was performed on the isolated supermeres. Myc (AB9106), enolase-1 (3810T), enolase-2 (8171S), and CD81 (EXOAB-CD81A1) antibodies were each used after being diluted 1:100, and 3 pg of each substance was loaded to confirm protein expression. As a result, T7-TGFBI-Myc supermeres exhibited a protein expression pattern similar to that of TGFBI-Myc supermeres (FIG. 21). These results suggest that a supermere marker such as TGFBI functions as a protein involved in the supermere formation process and enables the fused functional protein of interest to be selectively and effectively loaded into supermeres. From the above description, those skilled in the art to which the present invention belongs will understand that the present invention can be embodied in other specific forms without changing the technical idea or essential features thereof. In this regard, the examples described above should be understood as illustrative in all respects and not limiting. The scope of the present invention should be construed as including all modifications or variations derived from the meaning and scope of the claims described below and equivalent concepts thereof, rather than the detailed description above.

Claims

[CLAIMS]

1. A composition for delivering a functional substance, comprising a non-vesicular extracellular particle (NVEP) as an active ingredient.

2. The composition according to claim 1,wherein the non-vesicular extracellular particle is a supermere.

3. The composition according to claim 2,wherein the supermere has improved substance delivery ability relative to an extracellular vesicle or an exomere.

4. The composition according to claim 1,wherein the functional substance is in a protein form.

5. The composition according to claim 1,wherein the functional substance is in an RNA form.

6. The composition according to claim 1,wherein the functional substance is in a DNA form.

7. The composition according to claim 2,wherein the supermere is characterized by being accumulated in the liver in a smaller amount relative to an extracellular vesicle.

8. The composition according to claim 2,wherein the supermere is characterized by being accumulated in the spleen in a smaller amount relative to an extracellular vesicle.

9. A composition for delivering a functional substance, comprising a non-vesicular extracellular particle marker protein; and a non-vesicular extracellular particle comprising a functional substance of interest.

10. The composition according to claim 9,wherein the non-vesicular extracellular particle is a supermere.

11. The composition according to claim 10,wherein the supermere marker protein is one or more selected from the group consisting of transforming growth factor beta-induced (TGFBI), enolase-1 (ENO1), enolase-2 (ENO2), heat shock 70 kDa protein 13 (HSPA13), glucose-6-phosphate isomerase (GPI), lactate dehydrogenase A (LDHA), triosephosphate isomerase 1 (TPI1), hexokinase 1 (HK1), malate dehydrogenase 1 (MDH1), nucleobindin-1 (NUCB1), protein disulfide isomerase family A member 4 (PDIA4), fragments thereof, variants thereof, variants of fragments thereof, and fragments of variants thereof.

12. The composition according to claim 11,wherein the supermere marker protein is in a form fused with the functional substance of interest.

13. A pharmaceutical composition comprising the composition according to any one of claims 1 to 12.

14. A cosmetic composition comprising the composition according to any one ofclaims 1 to 12.

15. A kit for delivering a functional substance, comprising a non-vesicular extracellular particle (NVEP) as an active ingredient.

16. The kit according to claim 15,wherein the non-vesicular extracellular particle is a supermere.

17. Use of a composition for delivering a functional substance comprising a non-vesicular extracellular particle for delivering a functional substance.

18. Use of a non-vesicular extracellular particle for delivering a functional substance.

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