Therapeutic delivery compositions

Abstract

The present disclosure relates to polypeptides for targeting, purifying, and / or loading extracellular vesicles (EVs) such as exosomes. The present disclosure also relates to nucleic acids encoding said polypeptides, EVs comprising said polypeptides, methods of making and / or purifying said EVs, and medical uses of said EVs. The present disclosure also relates to EVs for targeting Schwann cells, methods of making and / or purifying said EVs, and medical uses of said EVs

Description

[0001]THERAPEUTIC DELIVERY COMPOSITIONS CROSS-REFRENCE TO RELATED APPLICATIONS This application claims the benefit of GB2408667.0, filed on 17 June 2024, and GB2411154.4, filed on 30 July 2024, each of which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates to polypeptides for targeting, purifying, and / or loading extracellular vesicles (EVs) such as exosomes. The present disclosure also relates to nucleic acids encoding said polypeptides, EVs comprising said polypeptides, methods of making and / or purifying said EVs, and medical uses of said EVs. The present disclosure also relates to nanoparticles and EVs for targeting Schwann cells, methods of making and / or purifying said nanoparticles and EVs, and medical uses of said nanoparticles and EVs BACKGROUND OF THE INVENTION A recent advance in the treatment of disease has been the rise of gene therapy and RNA therapeutics, such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology, RNA interference (RNAi) and mRNA delivery. This was spurred on by current limitations of conventional drug therapy targeting proteins. There are a limited number of druggable targets within proteins and coinciding with this only 1.5% of the human genome encodes for protein thus an alternative approach was necessary. A downfall of these new therapies is the need for an encapsulation vehicle for protection from nucleases, and many approaches have been designed. One method is the use of viral vectors such as adeno-associated vectors (AAVs) which can be engineered to deliver genetic information. Their small size makes tissue penetration easy and the use of AAVs results in high transduction efficiency, however repeat dosing is limited by their immunogenic response and cargo packaging capacity is low and limited to DNA-based molecules. Other packaging methods include lipid nanoparticles (LNPs), which are highly efficient in loading a large range of therapeutic modalities and produce minimal immunogenic response. Nonetheless, they can cause cytotoxicity and display rapid clearance following systemic administration. Virus like particles (VLPs) have also been investigated as they have a simple structure which is easy to engineer for specific targeting whilst producing little immunogenic responses. However, these have not been extensively used so require further study. Extracellular vesicles are produced and released by cells via secretion into the extracellular space. Once released, these vesicles are thought to play a role in cell-to-cell communication via their cargo carrying function (Zhang et al., 2019). Cargos that can be transported to recipient cells via extracellular vesicles include, protein, lipids, nucleic acids, and organelles such as mitochondria (Zaborowski et al., 2015) (Crewe et al., 2021). Extracellular vesicles can be categorised based on different characteristics such as size, function, content, and their relative release mechanism (Yáñez-Mó et al., 2015). Exosomes are one of the subsets of extracellular vesicles, with characteristics such as a diameter of 40-160 nm and production via multivesicular bodies (MVBs) within the producer cells (Kalluri and LeBleu, 2020). EVs can also be characterised by the membrane enrichment of tetraspanins such as CD63, CD81 and CD9 (Yáñez-Mó et al., 2015). In recent times, EVs have been demonstrated as potential therapeutic agents through their cargo carrying ability, with special attention to the loading and delivery of messenger RNA (mRNA). The delivery of exogenous mRNA enables the expression of therapeutic proteins that may be lacking in disease and consequently result in symptomatic relief or disease resolution. However, limitations such as nuclease degradation, immunogenicity and tissue targeting all exist with this therapeutic approach (Rohner et al., 2022). EVs can be loaded with mRNA of interest via different methods, these include transfection into cells, electroporation of EVs and EV-liposome hybrids (Aslan et al., 2021). By encapsulating mRNA into EVs, mRNA is protected from nucleases and from eliciting immunogenic responses. A study demonstrated that both mRNA loaded and unloaded EVs originating from human embryonic kidney (HEK293T) cells did not induce an immune response in C57BL / 6 mice following a 3 week repeat dose treatment (Zhu et al., 2017). This highlights the appeal of using EVs in treating disease. Another benefit of EVs in drug delivery is the ease of targeting them to different tissues or cell types. EVs can be easily engineered to express targeting moieties on their membrane by transfection of producer cells. Many studies have proven this, such as the use of rabies viral glycoprotein (RVG) in order to target microglia for small interfering RNA (siRNA) delivery (Alvarez-Erviti et al., 2011). This targeting strategy was also used in a study whose primary aim was to investigate tools to improve exosome biogenesis, RNA packaging into EVs, EV secretion, targeting and mRNA delivery, these tools were named EXOsomal transfer into cells (EXOtic) devices (Kojima et al., 2018). These tools were incorporated into EVs via transfection and overexpression of the proteins in EV producer cells. To increase EV production and secretion, the group discovered that overexpression of six-transmembrane epithelial antigen of the prostate 3 (STEAP3), syndecan and a fragment of L-aspartate oxidase resulted in a 15 – 40-fold increase in EV production. In order to improve mRNA packaging into EVs an archaeal ribosomal protein L7Ae which binds to the C / D box structure in RNA was utilised. This protein was conjugated to the CD63 C terminus, and the target mRNA used included a C / D box structure in order to increase the chance of encapsulation into the EV via L7Ae. To further mRNA delivery into the target cell, connexin 43, a gap junction protein was introduced, and it was found that its constitutively active mutant (S368A) enabled information transfer through the formation of hexameric channels. The combination of devices and the targeting moiety RVG-lamp2b dramatically increased mRNA delivery of nanoluciferase (nLuc) as seen in Kojima et al., 2018. The development of tools such as L7Ae dependent mRNA loading and optimisation of EV targeting are promising steps forward for EV research, however limitations still exist. Heterogeneity of isolated EVs is an issue due to the presence of cargo being different between individual EVs and thus mRNA loading efficiency is not optimal. The expression of targeting moieties on individual EVs is also not consistent and therefore may result in cargo loaded EVs not reaching the desired target. This highlights the need to further develop this technology to overcome limitations. Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with mutations derived from haploinsufficiency of the NF1 gene (Boyd et al., 2009). The NF1 gene results in the production of the protein neurofibromin which is a GTPase-activating protein (GAP), functioning as a negative regulator of Ras signalling (Kahen et al., 2018). The estimated prevalence of NF1 is 1 in 3500 people, making it one of the most common genetic disorders. At the clinical level, NF1 is associated with a wide spectrum of clinical manifestations including the growth of benign tumours on patients’ peripheral nerves called cutaneous and plexiform neurofibromas that upon malignant transformation can progress to peripheral nerve sheath tumours with an extremely low survival rate (Gerber et al., 2009). Neurofibromas consist of multiple cell types including, Schwann cells, fibroblasts, perineural cells and mast cells. However, it is widely accepted that NF1 inactivation in Schwann cells is the key element of tumorigenesis (Zhu et al., 2002). Current treatments for this disease include annual neurological and ophthalmologic examinations, tumour removal and traditional cancer therapies, thus there is cause to develop less toxic and more effective treatment options (Gerber et al., 2009). SUMMARY OF THE INVENTION In a first aspect, there is provided a polypeptide comprising a targeting moiety and a portion of a tetraspanin-family protein, wherein the tetraspanin-family protein is an EV-associated protein, and wherein the polypeptide does not comprise the N-terminal domain of the tetraspanin-family protein and does not comprise TM1 of the tetraspanin- family protein. In examples, the tetraspanin-family protein is CD9, CD37, CD63, CD81, or CD82. The portion of a tetraspanin- family protein may be a trispanin polypeptide and / or comprise TM2, TM3, and TM4. The portion of a tetraspanin- family protein may adopt the “n” topology in a membrane. The tetraspanin-family protein may be CD63 and the polypeptide: i) may not comprise residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1, ii) may not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 2, and / or iii) may comprise or may be a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 3 or 4. The tetraspanin-family protein may be CD9 and the polypeptide: i) may not comprise residues 1-33, 1-35, 1-40, 1- 45, 1-50, or 1-55 of SEQ ID NO: 21; ii) may not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 25; and / or iii) may comprise or may be a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 26 or 27. The tetraspanin-family protein may be CD37 and the polypeptide: i) may not comprise residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22; ii) may not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 28; and / or iii) may comprise or may be a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 29 or 30. The tetraspanin-family protein may be CD81 and the polypeptide: i) may not comprise residues 1-33, 1-35, 1-40, 1-45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23; ii) may not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 31; and / or iii) may comprise or may be a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 32 or 33. The tetraspanin-family protein may be CD82 and the polypeptide: i) may not comprise residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24; ii) may not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 34; and / or iii) may comprise or may be a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 35 or 36. The targeting moiety may be capable of specifically binding to a target. The targeting moiety may be capable of specifically binding to a cell-surface marker of a target cell. The targeting moiety may be a binding protein, an antibody or antigen-binding fragment thereof, a single-chain variable fragment (scFv), or a single-domain antibody (sdAb). The targeting moiety may be capable of specifically binding to Plasminogen activator urokinase receptor (PLAUR), Fibroblast growth factor receptor 1 (FGFR1), or Galanin receptor (GALR1). The targeting moiety may be or may comprise SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The targeting moiety may also be a purification moiety. The polypeptide may further comprise a purification moiety. The purification moiety may comprise an epitope for an antibody. The purification moiety may not comprise an epitope that is also found on other proteins associated with EVs or exosomes. The purification moiety may not comprise an epitope that is found on other proteins associated with human EVs or human exosomes. The purification moiety may not comprise an epitope that is found on other proteins associated with cells for producing EVs or exosomes. The purification moiety may be or may comprise a FLAG tag, HA-tag, a polyhistidine-tag, or a Myc-Tag. The order of components, from N to C, may be the targeting moiety, optionally the purification moiety, and the portion of a tetraspanin-family protein. The polypeptide may further comprise a cargo-binding moiety. The cargo-binding moiety may be located to the C- terminal side of the portion of a tetraspanin-family protein. The cargo-binding moiety may be a protein domain or a polypeptide. The cargo-binding moiety may be capable of binding to nucleic acid molecules. The cargo-binding moiety may be capable of binding to the C / Dboxstructure in RNA. The cargo-binding moiety may be or may comprise a nucleic acid binding domain from or derived from a PUF or Cas endonuclease. The cargo-binding moiety may be or may comprise L7Ae or a derivative thereof. The cargo-binding moiety may comprise a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 8 and can bind to the C / Dboxstructure. In a second aspect, there is provided a nucleic acid molecule encoding a polypeptide according to the first aspect. In a third aspect, there is provided an extracellular vesicle (EV) comprising a polypeptide according to the first aspect. The extracellular vesicle may be an exosome. The extracellular vesicle or exosome may be obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell. The N-terminal end of the portion of a tetraspanin-family protein may be external to the EV and the C-terminal end of the portion of a tetraspanin-family protein may be internal to the EV. The EV may comprise a therapeutic agent. The polypeptide of the first aspect may be bound to a cargo, optionally wherein the cargo is a therapeutic agent, via the cargo-binding domain. In a fourth aspect, there is provided a method of making an EV of the third aspect. The method may comprise: i) transferring a vector encoding a polypeptide of the first aspect to a cell suitable for producing EVs, and ii) obtaining EVs from said cell. In a fifth aspect, there is provided a method of purifying an EV of the third aspect. The method may comprise: i) obtaining a population comprising EVs according to the third aspect, ii) contacting the population comprising EVs with a binding agent that can specifically bind to the polypeptide of the first aspect; and iii) isolating EVs bound to said binding agent. In a sixth aspect, there is provided a pharmaceutical composition comprising a polypeptide of the first aspect, an EV of the third aspect, or an EV made according to the fourth or fifth aspects. In a seventh aspect, there is provided a polypeptide of the first aspect, an EV of the third aspect, an EV made according to the fourth or fifth aspects, or a pharmaceutical composition of the sixth aspect for use as a medicament. In examples, the medicament is used in a method for treating: a pathology associated with Schwann cells, a Schwann cell tumour, a Schwannosis, a Schwannoma, or Charcot-Marie-Tooth disease. The method may be for treating Neurofibromatosis type 1 (NF1). In an eighth aspect, there is provided a polypeptide that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent and at least a portion of an EV-associated protein. In a ninth aspect, there is provided a nucleic acid molecule encoding a polypeptide of the eighth aspect. In a tenth aspect, there is provided a nanoparticle or an EV that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The GALR1 binding agent may or may comprise SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The EV may be obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell. The EV may be an exosome obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell. The nanoparticle may be a lipid nanoparticle (LNP). The nanoparticle or EV may comprise a therapeutic agent. The therapeutic agent may be a nucleic acid encoding neurofibromin or a portion or variant thereof. The therapeutic agent may be or may comprise a nucleic acid molecule encoding SEQ ID NO: 13 or a portion or variant thereof. The therapeutic agent may be or may comprise a nucleic acid molecule encoding a polypeptide at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 or 16. The therapeutic agent may be or may comprise a nucleic acid molecule comprising a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 19 or 20. In an eleventh aspect, there is provided a method of making a nanoparticle or an EV of the tenth aspect. The method may comprise: i) transferring a vector encoding a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs; and ii) obtaining EVs from said cell. In a twelfth aspect, there is provided a method of purifying a nanoparticle or an EV of the tenth aspect. The method may comprise: i) obtaining a population comprising EVs of the tenth aspect, ii) contacting the population comprising EVs with a purification binding agent that can specifically bind to the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent or can specifically bind to a purification moiety; and iii) isolating EVs bound to said purification binding agent. In a thirteenth aspect, there is provided a pharmaceutical composition comprising a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, or a nanoparticle or an EV made according to the eleventh or twelfth aspects. In a fourteenth aspect, there is provided a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, a nanoparticle or an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use as a medicament. In examples, the medicament is used in a method for treating: a pathology associated with Schwann cells, a Schwann cell tumour, a Schwannosis, a Schwannoma, or Charcot-Marie-Tooth disease. The method may be for treating Neurofibromatosis type 1 (NF1). In a particular embodiment, there is provided an EV for use in a method of treating NF1, wherein the EV displays a galanin peptide or variant thereof on the outside of the EV, and the EV comprises a nucleic acid that encodes neurofibromin or a portion or variant thereof, wherein the neurofibromin, portion, or variant has GTPase-activating activity. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Design of engineered tetraspanin chimeras. A.- Cartoon depicting topology of native tetraspanins. Transmembrane domains are marked as TM (right) and predicted ‘n’ conformation, upon deletion of TM1 (right). B.- Protein alignment of the main tetraspanins frequently identified in exosomes. C.- Cartoon depicting T-REX construct design (top) and predicted topology at the protein level (bottom). D.- T-REX protein structure, predicted by META AI software. Location of FLAG and L7Ae is indicated. Figure 2. T-REX chimeras are expressed and load mRNA into exosomes. A.- Western blot of lysates from purified exosomes upon overexpression of native CD63, ‘n’ CD63 without N-terminal ligand and ‘n’ CD63 with N-terminal ligand. B.- Cartoon depicting mRNA of indicated lengths, containing C / D boxes. C.- RT-qPCR analysis of exosome loading, depending on mRNA size. Gapdh as a housekeeper using Sybr green master mix. D.- The effect of different targeting / loading constructs on exosome size. Size of exosomes determined by nanoparticle tracking analysis (Particle Metrix-Zetaview). E.- Cartoon depicting ligands of indicated sizes. F.- RT-qPCR analysis of exosome loading, depending on external targeting ligand. Gapdh as a housekeeper using Sybr green master mix. Data is expressed as fold change compared to native CD63. Figure 3. Galanin receptor provides targeting opportunities in neurofibromatosis type 1. A.- Single-cell gene expression data from human neurofibromas, including cell-type annotations and Uniform manifold approximation and projections (UMAP) coordinates were obtained from dataset GSE163028 (https: / / www.ncbi.nlm.nih.gov / geo / query / acc.cgi?acc=GSE163028). B.- Violin plots of relevant genes in different cell-type annotations. C.- UMAPs of relevant extracellular receptor genes in cell-types identified in neurofibromas. D.- Cartoon, depicting strategy to test the effect of galanin receptor / ligand expression on T-REX activity. Expression of galanin receptor was evaluated by qPCR. E.- Evaluation of nanoluc delivery by T-REX exosomes using a NanoGlo luciferase assay. HEK293F cells were transfected with T-REX construct with galanin ligand, plus nanoluciferase C / D box mRNA. Both orientations of galanin 1-30aa ligands were tested. Exosomes were isolated and applied to Schwann cells at 1e6 exosomes per well for 24 hours and a NanoGlo luciferase assay ran. Results are shown as mean^SEM. Statistical significance was evaluated by unpaired student’s T-test (* p<0.05). Figure 4 - T-REX actively loads mRNA and delivers it to cells. A. - Confocal microscopy images of Hela cells treated with either Wild Type (WT ) exosomes or T-REX exosomes which have been loaded with mango II x 9 RNA aptamer. Following 1 h treatment cells were fixed and stained with DAPI and mango RNA was visualised with T01-B. Images were taken with a 63x oil immersion objective. Scale bar indicates 100 µm. B. - Confocal microscopy images of Schwann cells that have either been non-treated or treated with exosomes loaded with mango II x 9 RNA aptamer by passive loading or active loading using T-REX. Exosomes were stained with APC- CD63, APC CD-81 and APC-CD-9. Following 1 h treatment cells were fixed and stained with DAPI and mango RNA was visualised with T01-B. Images were taken with a 63x oil immersion objective. Scale bar indicates 100 µm. C.- Gel electrophoresis assay showing free mango II x 9 RNA, WT exosomes, T-REX mango loaded exosomes treated with or without RNAse. Figure 5 - Cellular uptake of T-REX exosomes. A.- Confocal microscopy images of Schwann cells with or without GALR1 expression that have been treated with exosomes expressing the T-REX construct containing the galanin ligand. Exosomes were stained with APC-CD63, APC CD-81 and APC-CD-9. Following 1 h treatment cells were fixed and stained with DAPI. Images were taken with a 63x oil immersion objective. Scale bar indicates 100 µm. B. - Comparison of average APC foci per cell from experiment represented by images in A. Data shown represents mean ±SEM and statistical significance determined using an unpaired t-test, *p < 0.0332, ns < 0.1234. C. - Effect of various inhibitors on exosome cellular uptake as assessed by flow cytometry. Schwann cells possessing GALR1 expression were treated with inhibitors for 1 h. Cells were then treated with Galanin T- REX EVs stained with APC-CD63, APC-CD81 and APC-CD9 for 1 h and then assessed using flow cytometry. Data shows 3 technical repeats from the same experiment (n = 1). Data shown represents mean ± SEM and statistical significance determined using a one-way ANOVA ****p < 0.0001, ***p < 0.0002, **p < 0.0021, *p < 0.0332, ns < 0.1234. D. - Diagram demonstrating the cellular uptake pathways that are utilised for EV internalisation. Red lines show the pathways that are inhibited by the inhibitors that have been used in C. DETAILED DESCRIPTION Provided herein are chimeric proteins that can be used to target extracellular vesicles (EVs) to specific tissues, organs, or cells. These chimeric proteins include portions of the tetraspanin family, which is a family of transmembrane proteins that is known to be associated with extracellular vesicles. In an illustrative example of the above concept, the inventors have engineered a chimeric protein designed to combine EV targeting and RNA loading to increase cargo delivery and reduce EV heterogeneity. In a first aspect, there is provided a polypeptide comprising a targeting moiety and a portion of a tetraspanin-family protein, wherein the tetraspanin-family protein is an EV-associated protein, and wherein the polypeptide does not comprise the N-terminal domain of the tetraspanin-family protein and does not comprise TM1 of the tetraspanin- family protein. An EV-associated protein is a protein that is present in or enriched in EVs. The EV-associated protein may be a protein that is present in or enriched in exosomes. For instance, human exosomes are known to be enriched for certain proteins, and the polypeptide of the first aspect may comprise a portion of one of said proteins. Methods of making EVs or exosomes are provided herein, and the EV-associated protein may be any protein that is present in EVs or exosomes produced by said methods. The EV-associated protein may be any protein that is enriched in EVs or exosomes produced by said methods. The EV-associated protein may be any protein that is present in more than 50%, 60%, 70%, 80%, 90%, 95%, or 99% EVs or exosomes produced by said methods and which is detectable by flow cytometry. The tetraspanin family is also known as the transmembrane 4 superfamily. The tetraspanin-family protein may be any one of CD9, CD37, CD63, CD81, or CD82. In a particular embodiment, the tetraspanin-family protein is CD63, and this protein is discussed in the Examples section. For any of the aspects herein, the proteins may be matched to the subject to be treated. For instance, the proteins may be human proteins for the intended treatment of humans. Thus, the tetraspanin-family protein may be any one of human CD9, human CD37, human CD63, human CD81, or human CD82. Thus, in an embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD9, CD37, CD63, CD81, or CD82, wherein the polypeptide does not comprise the N-terminal domain of CD9, CD37, CD63, CD81, or CD82 and does not comprise TM1 of CD9, CD37, CD63, CD81, or CD82. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD63, wherein the polypeptide does not comprise the N-terminal domain of CD63 and does not comprise TM1 of CD63. As illustrated in an exemplary embodiment in Figure 1A, in these embodiments the polypeptide does not comprise the first transmembrane domain of the tetraspanin protein (TM1) nor the sequences that are positioned to the N- terminal side of TM1. The polypeptide may comprise TM2, TM3, and TM4 of the tetraspanin protein (i.e. the second, third, and fourth transmembrane domains). Such polypeptides will, therefore, cross the membrane three times and so may be referred to as a trispanin polypeptide. In these embodiments, when the polypeptide is present in a membrane (e.g. of an extracellular vesicle such as an exosome), the N-terminal end of the portion of a tetraspanin protein is external and the C-terminal end of the portion of a tetraspanin protein is internal. This arrangement may be referred to as the “n” topology, and is discussed further in Curley et al. (Nanoscale, 2020 June 11; 12(22): 12014-12026 – herein incorporated by reference). An exemplary sequence of CD63 is provided below as SEQ ID NO: 1. The transmembrane domains are underlined. MAVEGGMKCVKFLLYVLLLAFCACAVGLIAVGVGAQLVLSQTIIQGATPGSLLPVVIIAVGVFLFLVAFVGCCGAC KENYCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNNFRQQMENYPKNNHTASILDRMQADFKCCGAANYT DWEKIPSMSKNRVPDSCCINVTVGCGINFNEKAIHKEGCVEKIGGWLRKNVLVVAAAALGIAFVEVLGIVFACCLV KSIRSGYEVM (SEQ ID NO: 1) In some examples of embodiments comprising a portion of CD63, the polypeptide does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1. In a particular example, the polypeptide does not comprise residues 1-46 of SEQ ID NO: 1. These residues are provided herein as SEQ ID NO: 2 (below) and so, in some examples, the polypeptide does not comprise SEQ ID NO: 2. The polypeptide may not comprise a sequence that is similar to SEQ ID NO: 2 and so, in some embodiments, the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 2. Alignment for the comparison should include the full length of SEQ ID NO: 2. MAVEGGMKCVKFLLYVLLLAFCACAVGLIAVGVGAQLVLSQTIIQG (SEQ ID NO: 2) The portion of CD63 may comprise SEQ ID NO: 3 (below). The portion of CD63 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 3. In some examples, the portion of CD63 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 3. In some examples, the portion of CD63 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1 but does comprise SEQ ID NO: 3. In further examples, the portion of CD63 does not comprise at least SEQ ID NO: 2 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 3. LLPVVIIAVGVFLFLVAFVGCCGACKENYCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNNFRQQMENYP KNNHTASILDRMQADFKCCGAANYTDWEKIPSMSKNRVPDSCCINVTVGCGINFNEKAIHKEGCVEKIGGWLRKNV LVVAAAALGIAFVEVLGIVFACCLVKSIRSGYEVM (SEQ ID NO: 3) As exemplified herein, the portion of CD63 may comprise SEQ ID NO: 4 (below). The portion of CD63 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 4. In some examples, the portion of CD63 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 4. In some examples, the portion of CD63 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO: 1 but does comprise SEQ ID NO: 4. In further examples, the portion of CD63 does not comprise at least SEQ ID NO: 2 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 4. In a particular embodiment, the portion of CD63 does not comprise at least SEQ ID NO: 2 but does comprise SEQ ID NO: 4. ATPGSLLPVVIIAVGVFLFLVAFVGCCGACKENYCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNNFRQQ MENYPKNNHTASILDRMQADFKCCGAANYTDWEKIPSMSKNRVPDSCCINVTVGCGINFNEKAIHKEGCVEKIGGW LRKNVLVVAAAALGIAFVEVLGIVFACCLVKSIRSGYEVM (SEQ ID NO: 4) In some embodiments, the portion of CD63 is SEQ ID NO: 4. This portion may be fused to other polypeptide sequences but is not flanked by further sequence from CD63. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD63, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 2 and wherein the portion of CD63 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 4. Exemplary sequences of CD9, CD37, CD81, and CD82 (respectively) are provided below as SEQ ID NO: 1. The transmembrane domains are underlined. MPVKGGTKCIKYLLFGFNFIFWLAGIAVLAIGLWLRFDSQTKSIFEQETNNNNSSFYTGVYILIGAGALMMLVGFL GCCGAVQESQCMLGLFFGFLLVIFAIEIAAAIWGYSHKDEVIKEVQEFYKDTYNKLKTKDEPQRETLKAIHYALNC CGLAGGVEQFISDICPKKDVLETFTVKSCPDAIKEVFDNKFHIIGAVGIGIAVVMIFGMIFSMILCCAIRRNREMV (CD9 - SEQ ID NO: 21) MSAQESCLSLIKYFLFVFNLFFFVLGSLIFCFGIWILIDKTSFVSFVGLAFVPLQIWSKVLAISGIFTMGIALLGC VGALKELRCLLGLYFGMLLLLFATQITLGILISTQRAQLERSLRDVVEKTIQKYGTNPEETAAEESWDYVQFQLRC CGWHYPQDWFQVLILRGNGSEAHRVPCSCYNLSATNDSTILDKVILPQLSRLGHLARSRHSADICAVPAESHIYRE GCAQGLQKWLHNNLISIVGICLGVGLLELGFMTLSIFLCRNLDHVYNRLARYR (CD37 - SEQ ID NO: 22) MGVEGCTKCIKYLLFVFNFVFWLAGGVILGVALWLRHDPQTTNLLYLELGDKPAPNTFYVGIYILIAVGAVMMFVG FLGCYGAIQESQCLLGTFFTCLVILFACEVAAGIWGFVNKDQIAKDVKQFYDQALQQAVVDDDANNAKAVVKTFHE TLDCCGSSTLTALTTSVLKNNLCPSGSNIISNLFKEDCHQKIDDLFSGKLYLIGIAAIVVAVIMIFEMILSMVLCC GIRNSSVY (CD81 - SEQ ID NO: 23) MGSACIKVTKYFLFLFNLIFFILGAVILGFGVWILADKSSFISVLQTSSSSLRMGAYVFIGVGAVTMLMGFLGCIG AVNEVRCLLGLYFAFLLLILIAQVTAGALFYFNMGKLKQEMGGIVTELIRDYNSSREDSLQDAWDYVQAQVKCCGW VSFYNWTDNAELMNRPEVTYPCSCEVKGEEDNSLSVRKGFCEAPGNRTQSGNHPEDWPVYQEGCMEKVQAWLQENL GIILGVGVGVAIIELLGMVLSICLCRHVHSEDYSKVPKY (CD82 - SEQ ID NO: 24) In some examples of embodiments comprising a portion of CD9, the polypeptide does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21. In a particular example, the polypeptide does not comprise residues 1-50 of SEQ ID NO: 21. These residues are provided herein as SEQ ID NO: 25 (below) and so, in some examples, the polypeptide does not comprise SEQ ID NO: 25. The polypeptide may not comprise a sequence that is similar to SEQ ID NO: 25 and so, in some embodiments, the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 25. Alignment for the comparison should include the full length of SEQ ID NO: 25. MPVKGGTKCIKYLLFGFNFIFWLAGIAVLAIGLWLRFDSQTKSIFEQETN (SEQ ID NO: 25) The portion of CD9 may comprise SEQ ID NO: 26 (below). The portion of CD9 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 26. In some examples, the portion of CD9 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 26. In some examples, the portion of CD9 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21 but does comprise SEQ ID NO: 26. In further examples, the portion of CD9 does not comprise at least SEQ ID NO: 25 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 26. FYTGVYILIGAGALMMLVGFLGCCGAVQESQCMLGLFFGFLLVIFAIEIAAAIWGYSHKDEVIKEVQEFYKDTYNK LKTKDEPQRETLKAIHYALNCCGLAGGVEQFISDICPKKDVLETFTVKSCPDAIKEVFDNKFHIIGAVGIGIAVVM IFGMIFSMILCCAIRRNREMV (SEQ ID NO: 26) The portion of CD9 may comprise SEQ ID NO: 27 (below). The portion of CD9 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 27. In some examples, the portion of CD9 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 27. In some examples, the portion of CD9 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21 but does comprise SEQ ID NO: 27. In further examples, the portion of CD9 does not comprise at least SEQ ID NO: 25 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 27. In a particular embodiment, the portion of CD9 does not comprise at least SEQ ID NO: 25 but does comprise SEQ ID NO: 27. NNNSSFYTGVYILIGAGALMMLVGFLGCCGAVQESQCMLGLFFGFLLVIFAIEIAAAIWGYSHKDEVIKEVQEFYK DTYNKLKTKDEPQRETLKAIHYALNCCGLAGGVEQFISDICPKKDVLETFTVKSCPDAIKEVFDNKFHIIGAVGIG IAVVMIFGMIFSMILCCAIRRNREMV (SEQ ID NO: 27) In some embodiments, the portion of CD9 is SEQ ID NO: 27. This portion may be fused to other polypeptide sequences but is not flanked by further sequence from CD9. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD9, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 25 and wherein the portion of CD9 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 27. In some examples of embodiments comprising a portion of CD37, the polypeptide does not comprise at least residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22. In a particular example, the polypeptide does not comprise residues 1-48 of SEQ ID NO: 22. These residues are provided herein as SEQ ID NO: 28 (below) and so, in some examples, the polypeptide does not comprise SEQ ID NO: 28. The polypeptide may not comprise a sequence that is similar to SEQ ID NO: 28 and so, in some embodiments, the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 28. Alignment for the comparison should include the full length of SEQ ID NO: 28. MSAQESCLSLIKYFLFVFNLFFFVLGSLIFCFGIWILIDKTSFVSFVG (SEQ ID NO: 28) The portion of CD37 may comprise SEQ ID NO: 29 (below). The portion of CD37 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 29. In some examples, the portion of CD37 does not comprise at least residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 29. In some examples, the portion of CD37 does not comprise at least residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22 but does comprise SEQ ID NO: 29. In further examples, the portion of CD37 does not comprise at least SEQ ID NO: 28 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 29. VLAISGIFTMGIALLGCVGALKELRCLLGLYFGMLLLLFATQITLGILISTQRAQLERSLRDVVEKTIQKYGTNPE ETAAEESWDYVQFQLRCCGWHYPQDWFQVLILRGNGSEAHRVPCSCYNLSATNDSTILDKVILPQLSRLGHLARSR HSADICAVPAESHIYREGCAQGLQKWLHNNLISIVGICLGVGLLELGFMTLSIFLCRNLDHVYNRLARYR (SEQ ID NO: 29) As exemplified herein, the portion of CD37 may comprise SEQ ID NO: 30 (below). The portion of CD37 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 30. In some examples, the portion of CD37 does not comprise at least residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1- 59 of SEQ ID NO: 22 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 30. In some examples, the portion of CD37 does not comprise at least residues 1-38, 1- 40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22 but does comprise SEQ ID NO: 30. In further examples, the portion of CD37 does not comprise at least SEQ ID NO: 28 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 30. In a particular embodiment, the portion of CD37 does not comprise at least SEQ ID NO: 28 but does comprise SEQ ID NO: 30. LAFVPLQIWSKVLAISGIFTMGIALLGCVGALKELRCLLGLYFGMLLLLFATQITLGILISTQRAQLERSLRDVVE KTIQKYGTNPEETAAEESWDYVQFQLRCCGWHYPQDWFQVLILRGNGSEAHRVPCSCYNLSATNDSTILDKVILPQ LSRLGHLARSRHSADICAVPAESHIYREGCAQGLQKWLHNNLISIVGICLGVGLLELGFMTLSIFLCRNLDHVYNR LARYR (SEQ ID NO: 30) In some embodiments, the portion of CD37 is SEQ ID NO: 30. This portion may be fused to other polypeptide sequences but is not flanked by further sequence from CD37. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD37, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 28 and wherein the portion of CD37 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 30. In some examples of embodiments comprising a portion of CD81, the polypeptide does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23. In a particular example, the polypeptide does not comprise residues 1-52 of SEQ ID NO: 23. These residues are provided herein as SEQ ID NO: 31 (below) and so, in some examples, the polypeptide does not comprise SEQ ID NO: 31. The polypeptide may not comprise a sequence that is similar to SEQ ID NO: 31 and so, in some embodiments, the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 31. Alignment for the comparison should include the full length of SEQ ID NO: 31. MGVEGCTKCIKYLLFVFNFVFWLAGGVILGVALWLRHDPQTTNLLYLELGDK (SEQ ID NO: 31) The portion of CD81 may comprise SEQ ID NO: 32 (below). The portion of CD81 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 32. In some examples, the portion of CD81 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 32. In some examples, the portion of CD81 does not comprise at least residues 1-33, 1-35, 1-40, 1- 45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23 but does comprise SEQ ID NO: 32. In further examples, the portion of CD81 does not comprise at least SEQ ID NO: 31 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 32. ILIAVGAVMMFVGFLGCYGAIQESQCLLGTFFTCLVILFACEVAAGIWGFVNKDQIAKDVKQFYDQALQQAVVDDD ANNAKAVVKTFHETLDCCGSSTLTALTTSVLKNNLCPSGSNIISNLFKEDCHQKIDDLFSGKLYLIGIAAIVVAVI MIFEMILSMVLCCGIRNSSVY (SEQ ID NO: 32) The portion of CD81 may comprise SEQ ID NO: 33 (below). The portion of CD81 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 33. In some examples, the portion of CD81 does not comprise at least residues 1-33, 1-35, 1-40, 1-45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 33. In some examples, the portion of CD81 does not comprise at least residues 1-33, 1-35, 1-40, 1- 45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23 but does comprise SEQ ID NO: 33. In further examples, the portion of CD81 does not comprise at least SEQ ID NO: 31 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 33. In a particular embodiment, the portion of CD81 does not comprise at least SEQ ID NO: 31 but does comprise SEQ ID NO: 33. PAPNTFYVGIYILIAVGAVMMFVGFLGCYGAIQESQCLLGTFFTCLVILFACEVAAGIWGFVNKDQIAKDVKQFYD QALQQAVVDDDANNAKAVVKTFHETLDCCGSSTLTALTTSVLKNNLCPSGSNIISNLFKEDCHQKIDDLFSGKLYL IGIAAIVVAVIMIFEMILSMVLCCGIRNSSVY (SEQ ID NO: 33) In some embodiments, the portion of CD81 is SEQ ID NO: 33. This portion may be fused to other polypeptide sequences but is not flanked by further sequence from CD81. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD81, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 31 and wherein the portion of CD81 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 33. In some examples of embodiments comprising a portion of CD82, the polypeptide does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24. In a particular example, the polypeptide does not comprise residues 1-46 of SEQ ID NO: 24. These residues are provided herein as SEQ ID NO: 34 (below) and so, in some examples, the polypeptide does not comprise SEQ ID NO: 34. The polypeptide may not comprise a sequence that is similar to SEQ ID NO: 34 and so, in some embodiments, the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 34. Alignment for the comparison should include the full length of SEQ ID NO: 34. MGSACIKVTKYFLFLFNLIFFILGAVILGFGVWILADKSSFISVLQ (SEQ ID NO: 34) The portion of CD82 may comprise SEQ ID NO: 35 (below). The portion of CD82 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 35. In some examples, the portion of CD82 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 35. In some examples, the portion of CD82 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24 but does comprise SEQ ID NO: 35. In further examples, the portion of CD82 does not comprise at least SEQ ID NO: 34 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 35. MGAYVFIGVGAVTMLMGFLGCIGAVNEVRCLLGLYFAFLLLILIAQVTAGALFYFNMGKLKQEMGGIVTELIRDYN SSREDSLQDAWDYVQAQVKCCGWVSFYNWTDNAELMNRPEVTYPCSCEVKGEEDNSLSVRKGFCEAPGNRTQSGNH PEDWPVYQEGCMEKVQAWLQENLGIILGVGVGVAIIELLGMVLSICLCRHVHSEDYSKVPKY (SEQ ID NO: 35) The portion of CD82 may comprise SEQ ID NO: 36 (below). The portion of CD82 may comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 36. In some examples, the portion of CD82 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 36. In some examples, the portion of CD82 does not comprise at least residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24 but does comprise SEQ ID NO: 36. In further examples, the portion of CD82 does not comprise at least SEQ ID NO: 34 but does comprise a sequence with at least 80%, 85%, 90%, 95%, 99%, or 100% similarity or identity to SEQ ID NO: 36. In a particular embodiment, the portion of CD82 does not comprise at least SEQ ID NO: 34 but does comprise SEQ ID NO: 36. TSSSSLRMGAYVFIGVGAVTMLMGFLGCIGAVNEVRCLLGLYFAFLLLILIAQVTAGALFYFNMGKLKQEMGGIVT ELIRDYNSSREDSLQDAWDYVQAQVKCCGWVSFYNWTDNAELMNRPEVTYPCSCEVKGEEDNSLSVRKGFCEAPGN RTQSGNHPEDWPVYQEGCMEKVQAWLQENLGIILGVGVGVAIIELLGMVLSICLCRHVHSEDYSKVPKY (SEQ ID NO: 36) In some embodiments, the portion of CD82 is SEQ ID NO: 36. This portion may be fused to other polypeptide sequences but is not flanked by further sequence from CD82. In a particular embodiment, there is provided a polypeptide comprising a targeting moiety and a portion of CD82, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 34 and wherein the portion of CD82 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 36. The polypeptide of the first aspect comprises a targeting moiety. Thus, the polypeptide comprises both a portion of a tetraspanin-family protein and a targeting moiety. The polypeptide may be referred to as a chimeric polypeptide or a fusion protein. The targeting moiety may be positioned to the N-terminal side of the portion of a tetraspanin-family protein. As discussed herein, when the polypeptide is inserted in the membrane of an EV, such as an exosome, this will lead to the display of the targeting moiety on the outside of the EV. The targeting moiety may be any moiety that, when presented on the outside of an EV, such as an exosome, alters the distribution of the EV. For instance, a targeting moiety may alter the tissue distribution of an EV when administered to an organism, may alter the organ-distribution of an EV when administered to an organism, may alter the quantities of EVs found in specific organs when administered to an organism, or may affect the interaction between the EVs and a particular cell. In particular, the targeting moiety may be a cell-targeting moiety. EVs displaying the cell-targeting moiety interact with their target cells at a higher frequency compared to control EVs not displaying the cell-targeting moiety. EVs displaying the cell-targeting moiety will transfer any cargo carried by the EV to their target cells at a higher frequency compared to control EVs not displaying the cell-targeting moiety. In examples disclosed herein, the targeting moiety targets Schwann cells. To achieve the above-mentioned effects, the targeting moiety may be capable of specifically binding to a target. For instance, the targeting moiety may be capable of specifically binding to a cell-surface marker of a target cell. Examples of such targeting moieties include ligands that may be bound by cell-surface receptors. Alternatively, the targeting moiety may be a receptor capable of binding to a ligand on the target cell. The targeting moiety may be a binding protein, such as an antibody or antigen-binding fragment thereof or may be based on an antibody scaffold. The targeting moiety may be a single-chain variable fragment (scFv) of an antibody. The targeting moiety may be a single-domain antibody (sdAb), sometimes known as a nanobody. In some embodiments, the targeting moiety is capable of specifically binding to Plasminogen activator urokinase receptor (PLAUR), Fibroblast growth factor receptor 1 (FGFR1), or Galanin receptor (GALR1). As illustrated in Figure 3C, GALR1 is a particularly suitable target for targeting cells to Schwann cells. The targeting moiety may be a binding protein, such as an antibody (e.g. an sdAb) that is specific for PLAUR, FGFR1, or GALR1. In particular embodiments, the targeting moiety is a peptide capable of binding to GALR1 (see Example 3). The peptide may be or may comprise galanin. For instance, the peptide may be the 30 residues of galanin. The peptide may comprise SEQ ID NO: 5 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 5 with no more than 5, 4, 3, 2, 1, or no substitutions. The targeting moiety may be SEQ ID NO: 5 and so the polypeptide of the first aspect may comprise SEQ ID NO: 5. GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS (SEQ ID NO: 5) As demonstrated in the Examples, galanin functions as a targeting moiety in either direction. Thus, the galanin may be in either orientation in the polypeptide of the first aspect. The targeting moiety may be a peptide comprising SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 6 with no more than 5, 4, 3, 2, 1, or no substitutions. The targeting moiety may be SEQ ID NO: 6 and so the polypeptide of the first aspect may comprise SEQ ID NO: 6. STLGNKDSFSRHNGVAHPGLLYGASNLTWG (SEQ ID NO: 6) The targeting moiety may also function as a purification moiety. Thus, in some embodiments, the polypeptide of the first aspect comprises a targeting moiety that is also a purification moiety. The targeting moiety may be a polypeptide sequence of sufficient length so as to be targetable by a binding domain, such as an antibody or other binding protein. In addition, the targeting moiety may not comprise an epitope that is also found on other proteins associated with the EV. The targeting moiety may not comprise an epitope that is also found on other proteins associated with exosomes. The targeting moiety may not comprise an epitope that is also found on other proteins associated with human EVs or human exosomes. The targeting moiety may not comprise an epitope that is also found on other proteins associated with the cell for producing the EV or exosomes. The targeting moiety may not comprise an epitope that is also found on other proteins associated with human EVs, human exosomes, or producer cells for said EVs or exosomes. The polypeptide of the first aspect may comprise a purification moiety that is separate from the targeting moiety. In an embodiment, therefore, the polypeptide of the first aspect comprises a purification moiety. In some embodiments, the polypeptide of the first aspect comprises a targeting moiety and a separate purification moiety. The purification moiety may be a polypeptide of sufficient length so as to be targetable by a binding domain, such as an antibody or other binding protein. In addition, the purification moiety may not comprise an epitope that is also found on other proteins associated with the EV. The purification moiety may not comprise an epitope that is also found on other proteins associated with exosomes. The purification moiety may not comprise an epitope that is also found on other proteins associated with human EVs or human exosomes. The purification moiety may not comprise an epitope that is also found on other proteins associated with the cell for producing the EV or exosomes. The purification moiety may not comprise an epitope that is also found on other proteins associated with human EVs, human exosomes, or producer cells for said EVs or exosomes. In some examples, the purification moiety is or comprises a FLAG-tag. Anti-FLAG antibodies are commercially available and bind to the peptide sequence: DYKDDDDK (SEQ ID NO: 7). Other suitable epitope tags are known to the skilled person and could be applied to the polypeptide of the first aspect. For instance, the purification moiety may be or may comprise an HA-tag, a polyhistidine-tag, or a Myc-Tag. The purification moiety may be positioned to the N-terminal side of the portion of a tetraspanin-family protein. As discussed herein, when the polypeptide is inserted in the membrane of an EV, such as an exosome, this will lead to the display of the purification moiety on the outside of the EV. In some embodiments, the purification moiety is positioned to the C-terminal side of the targeting moiety. The order, from N to C, of components in the polypeptide of the first aspect is then: targeting moiety, purification moiety, and portion of a tetraspanin-family protein. In an embodiment, the order, from N to C, of components in the polypeptide of the first aspect is then: targeting moiety, purification moiety, and portion of CD63, wherein the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity to SEQ ID NO: 2 and wherein the portion of CD63 comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 4. The polypeptide of the first aspect may further comprise a cargo-binding moiety. Polypeptides with both the targeting moiety and the cargo-binding moiety can be used to deliver cargo, such as therapeutic agents, to target cells. The cargo-binding moiety may be positioned to the C-terminal side of the portion of a tetraspanin-family protein. As discussed herein, when the polypeptide is inserted in the membrane of an EV, such as an exosome, this will lead to the cargo-binding moiety being present on the inside of the EV. Thus, cargo can be loaded into the EV or retained in the EV. The order, from N to C, of components in the polypeptide of the first aspect may be: targeting moiety, portion of a tetraspanin-family protein, and cargo-binding moiety. In other embodiments, the order, from N to C, of components in the polypeptide of the first aspect may be: targeting moiety, purification moiety, portion of a tetraspanin-family protein, and cargo-binding moiety. In a particular embodiment, the order, from N to C, of components in the polypeptide of the first aspect may be: targeting moiety, portion of CD63, and cargo-binding moiety. In other embodiments, the order, from N to C, of components in the polypeptide of the first aspect may be: targeting moiety, purification moiety, portion of CD63, and cargo-binding moiety. There are many suitable cargo-binding moieties and they will vary depending on the cargo that is desired to be loaded. Thus, the cargo-binding moiety just needs to be capable of binding to a cargo. The cargo-binding moiety may be a protein domain or a polypeptide that is capable of specifically binding to a particular cargo. The cargo may be a therapeutic agent, such as a therapeutic protein or a therapeutic nucleic acid. A common cargo that is loaded into EVs and exosomes is a nucleic acid molecule. The nucleic acid may be suitable for causing a therapeutic change in gene expression in a target cell, for instance by editing the cell’s genome, by reducing expression of a gene or genes in a cell, by inhibiting translation of a specific mRNA or mRNAs in the cell, or by being translated within the cell. Thus, in embodiments, the cargo-binding moiety is capable of binding to nucleic acid molecules. The cargo-binding moiety may be capable of binding to DNA and / or RNA. The cargo-binding moiety may be capable of binding to mRNA. The cargo-binding moiety may be capable of binding to the C / Dboxstructure in RNA. The cargo-binding moiety be a polypeptide or a protein-domain that is capable of binding to nucleic acid molecules. The skilled person is aware of many suitable polypeptides and protein domains that are suitable for the above- mentioned purposes. For instance, domains derived from endonucleases or RNA and / or DNA binding proteins can be used to provide suitable nucleic acid binding domains. Examples include the PUF families and the Cas families of endonucleases. Hence, the cargo-binding moiety may be a nucleic acid binding domain from or derived from a PUF or Cas endonuclease. The cargo-binding moiety may comprise Pumby modules. The cargo-binding moiety may be or may comprise L7Ae or a derivative thereof. L7Ae is an archaeal ribosomal protein that binds to the C / Dboxstructure in RNA and an exemplary sequence is provided below. Thus, the polypeptide of the first aspect may comprise a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 8 and can bind to the C / Dboxstructure. MYVRFEVPEDMQNEALSLLEKVRESGKVKKGTNETTKAVERGLAKLVYIAEDVDPPEIVAHLPLLCEEKNVPYIYV KSKNDLGRAVGIEVPCASAAIINEGELRKELGSLVEKIKGLQK (SEQ ID NO: 8) As discussed, the order, from N to C, of components in the polypeptide of the first aspect may be: i) targeting moiety and portion of a tetraspanin-family protein; ii) targeting moiety, purification moiety, and portion of a tetraspanin- family protein; iii) targeting moiety, portion of a tetraspanin-family protein, and cargo-binding moiety; or iv) targeting moiety, purification moiety, portion of a tetraspanin-family protein, and cargo-binding moiety. These domains may be contiguous. Alternatively, and in the exemplifications disclosed herein, these domains are separated by linkers. The linkers may be short polypeptide sequences. The linkers may be flexible, for instance they may contain one or more glycine and / or one or more serine. One or more linker may be or may comprise a cleavage domain. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order, a targeting moiety, a portion of CD63, and a nucleic-acid-binding domain. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order, a targeting moiety, a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 4, and a nucleic-acid- binding domain. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions and a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 4. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 5, 4, 3, 2, 1, or no substitutions and a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 4. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions; a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 4; and a nucleic-acid-binding domain. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions; a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 4; and a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 8. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6 or with no more than 5, 4, 3, 2, 1, or no substitutions; a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 4; and a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 8. In a particular embodiment, there is disclosed a polypeptide comprising, in N to C order: SEQ ID NO: 5 or SEQ ID NO: 6, SEQ ID NO: 4, and SEQ ID NO: 8. An exemplary polypeptide of the first aspect is below. This polypeptide includes a galanin peptide, a FLAG-tag, a linker, a portion of CD63, a linker, and L7Ae. Thus, the polypeptide of the first aspect may be or may comprise a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 9. MGWTLNSAGYLLGPHAVGNHRSFSDKNGLTSDYKDDDDKKLATATPGSLLPVVIIAVGVFLFLVAFVGCCGACKEN YCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNNFRQQMENYPKNNHTASILDRMQADFKCCGAANYTDWE KIPSMSKNRVPDSCCINVTVGCGINFNEKAIHKEGCVEKIGGWLRKNVLVVAAAALGIAFVEVLGIVFACCLVKSI RSGYEVMEFGGGGSMYVRFEVPEDMQNEALSLLEKVRESGKVKKGTNETTKAVERGLAKLVYIAEDVDPPEIVAHL PLLCEEKNVPYIYVKSKNDLGRAVGIEVPCASAAIINEGELRKELGSLVEKIKGLQK (SEQ ID NO: 9) Another exemplary polypeptide of the first aspect is below. This polypeptide includes an inverse galanin peptide, a FLAG-tag, a linker, a portion of CD63, a linker, and L7Ae. Thus, the polypeptide of the first aspect may be or may comprise a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 10. MSTLGNKDSFSRHNGVAHPGLLYGASNLTWGDYKDDDDKKLATATPGSLLPVVIIAVGVFLFLVAFVGCCGACKEN YCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNNFRQQMENYPKNNHTASILDRMQADFKCCGAANYTDWE KIPSMSKNRVPDSCCINVTVGCGINFNEKAIHKEGCVEKIGGWLRKNVLVVAAAALGIAFVEVLGIVFACCLVKSI RSGYEVMEFGGGGSMYVRFEVPEDMQNEALSLLEKVRESGKVKKGTNETTKAVERGLAKLVYIAEDVDPPEIVAHL PLLCEEKNVPYIYVKSKNDLGRAVGIEVPCASAAIINEGELRKELGSLVEKIKGLQK (SEQ ID NO: 10) In a second aspect, there is provided a nucleic acid molecule encoding a polypeptide of the first aspect. The nucleic acid may be part of a vector. The vector may include an expression cassette. For instance, a promoter operably linked to the gene encoding the polypeptide of the first aspect. A purely illustrative construct encoding a polypeptide of the first aspect is presented below. This construct includes, in order, a galanin peptide, FLAG-tag, a CD63 portion, and L7Ae. The bold “ATG” in the above is the start codon of the polypeptide. The bold “tga” is the stop codon. ATGGGCTGGACTCTCAATTCTGCTGGTTACCTGCTGGGCCCTCACGCGGTAGGGAACCACCGGTCATTCTCAGATA AGAACGGACTTACCAGTGATTACAAGGATGACGACGATAAGaagcttgccaccgctacccctggctctctgttgcc agtggtcatcatcgcagtgggtgtcttcctcttcctggtggcttttgtgggctgctgcggggcctgcaaggagaac tattgtcttatgatcacgtttgccatctttctgtctcttatcatgttggtggaggtggccgcagccattgctggct atgtgtttagagataaggtgatgtcagagtttaataacaacttccggcagcagatggagaattacccgaaaaacaa ccacactgcttcgatcctggacaggatgcaggcagattttaagtgctgtggggctgctaactacacagattgggag aaaatcccttccatgtcgaagaaccgagtccccgactcctgctgcattaatgttactgtgggctgtgggattaatt tcaacgagaaggcgatccataaggagggctgtgtggagaagattgggggctggctgaggaaaaatgtgctggtggt agctgcagcagcccttggaattgcttttgtcgaggttttgggaattgtctttgcctgctgcctcgtgaagagtatc agaagtggctacgaggtgatggaattcggcggaggcgggtccatgtacgtgcgcttcgaggtgcccgaggacatgc agaacgaggccctgagcctgctggaaaaagtgcgcgagagcggcaaagtgaagaagggcaccaacgaaaccaccaa ggccgtggaacggggcctggccaagctggtgtatatcgccgaggacgtggacccccccgagattgtggcccatctg cccctgctgtgcgaagagaagaacgtgccctacatctacgtgaagtccaagaacgacctgggcagagccgtgggca tcgaggtgccatgtgcctctgccgccatcatcaacgagggcgagctgcggaaagaactgggcagcctggtggaaaa gatcaagggcctgcagaagtga (SEQ ID NO: 11) Another purely illustrative construct encoding a polypeptide of the first aspect is presented below. This construct includes, in order, an inverted galanin peptide, FLAG-tag, a CD63 portion, and L7Ae. The bold “ATG” in the above is the start codon of the polypeptide. The bold “tga” is the stop codon. ATGAGCACGTTGGGAAACAAAGATTCCTTCTCACGGCATAACGGGGTAGCTCATCCAGGGTTGCTGTATGGAGCCT CCAATCTCACATGGGGAGATTACAAGGATGACGACGATAAGaagcttgccaccgctacccctggctctctgttgcc agtggtcatcatcgcagtgggtgtcttcctcttcctggtggcttttgtgggctgctgcggggcctgcaaggagaac tattgtcttatgatcacgtttgccatctttctgtctcttatcatgttggtggaggtggccgcagccattgctggct atgtgtttagagataaggtgatgtcagagtttaataacaacttccggcagcagatggagaattacccgaaaaacaa ccacactgcttcgatcctggacaggatgcaggcagattttaagtgctgtggggctgctaactacacagattgggag aaaatcccttccatgtcgaagaaccgagtccccgactcctgctgcattaatgttactgtgggctgtgggattaatt tcaacgagaaggcgatccataaggagggctgtgtggagaagattgggggctggctgaggaaaaatgtgctggtggt agctgcagcagcccttggaattgcttttgtcgaggttttgggaattgtctttgcctgctgcctcgtgaagagtatc agaagtggctacgaggtgatggaattcggcggaggcgggtccatgtacgtgcgcttcgaggtgcccgaggacatgc agaacgaggccctgagcctgctggaaaaagtgcgcgagagcggcaaagtgaagaagggcaccaacgaaaccaccaa ggccgtggaacggggcctggccaagctggtgtatatcgccgaggacgtggacccccccgagattgtggcccatctg cccctgctgtgcgaagagaagaacgtgccctacatctacgtgaagtccaagaacgacctgggcagagccgtgggca tcgaggtgccatgtgcctctgccgccatcatcaacgagggcgagctgcggaaagaactgggcagcctggtggaaaa gatcaagggcctgcagaagtga (SEQ ID NO: 12) In an embodiment, there is provided a nucleic acid construct comprising a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 11 or SEQ ID NO: 12. In an embodiment, there is provided a nucleic acid construct comprising a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 11 or SEQ ID NO: 12, and wherein no more than 40, 30, 20, 10, 5, 3, 2, 1, or no codons are only exchanged for non- synonymous codons. The polypeptides of the first aspect are suitable for use in EVs, particularly in exosomes. Thus, in a third aspect, there is provided an extracellular vesicle comprising a polypeptide of the first aspect. The EV may be a vesicle that is produced by a cell and can be purified, and which can be maintained extracellularly. The cell may be a eukaryotic cell. The cell may be from the same species as the subject for which the EV is intended to treat. Thus, the EV may be a vesicle that is produced by a mammalian cell or by a human cell. The EV may be a vesicle that is released extracellularly, e.g. into the supernatant of a culture, by a cell. The cell may be a eukaryotic cell. The cell may be from the same species as the subject for which the EV is intended to treat. Thus, the EV may be a vesicle that is released extracellularly, e.g. into the supernatant of a culture, by a mammalian cell or a human cell. In particular embodiments, the EV is an exosome. Again, the exosome may be obtained or obtainable from a cell that is of same species as the subject for which the exosome is intended to treat. The cell may be a eukaryotic cell. The exosome may be obtained or obtainable from a mammalian cell or a human cell. The portion of a tetraspanin-family protein may adopt the “n” topology in the membrane of the EV or exosome. Thus, the targeting moiety and optionally the purification moiety may be positioned on the outside of the EV or exosome. Where present, the cargo-binding moiety is present inside the EV or exosome. In a particular embodiment, the polypeptide comprises a nucleic acid binding domain and the EV is loaded with a nucleic acid cargo. The nucleic acid cargo may be mRNA or an analogue. The cargo may be less than 8.5kb. The cargo may be less than 7kb, 6kb, 5kb, 4kb, or 3kb. The cargo may be less than 1.5kb. The cargo may comprise one or more modified sugar moieties. For instance, the 2’ position of one or more sugar moieties within the nucleic acid cargo may be modified. In addition, the 4’ position may be modified (e.g. locked nucleic acids). The cargo may comprise one or more modified linkages between monomers. The cargo may comprise one or more modified nucleobases. Thus, the cargo may be a nucleic acid analogue. The nucleic acid cargo may encode neurofibromin or a portion or variant thereof. The cargo may be mRNA or an analogue encoding neurofibromin or a portion or variant thereof. The cargo may encode a portion of neurofibromin that retains its function as a GTPase-activating protein. The cargo may encode a hyperactive variant of neurofibromin. The cargo may encode a variant of neurofibromin disclosed in Bai et al. Gen Ther. 2019 Jun; 26 (6) (herein incorporated by reference). The mRNA cargo may be approximately 1 to 1.4, approximately 1.1 to 1.3, or approximately 1.2 kb. The mRNA cargo may be 1.197 kb. In a particular embodiment the EV is loaded with a nucleic acid molecule encoding SEQ ID NO: 13 (shown below) or a portion or variant thereof. The portion or variant may be a polypeptide with GTPase-activation activity. The portion or variant may comprise separate regions of SEQ ID NO: 13 fused together. MAAHRPVEWVQAVVSRFDEQLPIKTGQQNTHTKVSTEHNKECLINISKYKFSLVISGLTTILKNVNNMRIFGEAAE KNLYLSQLIILDTLEKCLAGQPKDTMRLDETMLVKQLLPEICHFLHTCREGNQHAAELRNSASGVLFSLSCNNFNA VFSRISTRLQELTVCSEDNVDVHDIELLQYINVDCAKLKRLLKETAFKFKALKKVAQLAVINSLEKAFWNWVENYP DEFTKLYQIPQTDMAECAEKLFDLVDGFAESTKRKAAVWPLQIILLILCPEIIQDISKDVVDENNMNKKLFLDSLR KALAGHGGSRQLTESAAIACVKLCKASTYINWEDNSVIFLLVQSMVVDLKNLLFNPSKPFSRGSQPADVDLMIDCL VSCFRISPHNNQHFKICLAQNSPSTFHYVLVNSLHRIITNSALDWWPKIDAVYCHSVELRNMFGETLHKAVQGCGA HPAIRMAPSLTFKEKVTSLKFKEKPTDLETRSYKYLLLSMVKLIHADPKLLLCNPRKQGPETQGSTAELITGLVQL VPQSHMPEIAQEAMEALLVLHQLDSIDLWNPDAPVETFWEISSQMLFYICKKLTSHQMLSSTEILKWLREILICRN KFLLKNKQADRSSCHFLLFYGVGCDIPSSGNTSQMSMDHEELLRTPGASLRKGKGNSSMDSAAGCSGTPPICRQAQ TKLEVALYMFLWNPDTEAVLVAMSCFRHLCEEADIRCGVDEVSVHNLLPNYNTFMEFASVSNMMSTGRAALQKRVM ALLRRIEHPTAGNTEAWEDTHAKWEQATKLILNYPKAKMEDGQAAESLHKTIVKRRMSHVSGGGSIDLSDTDSLQE WINMTGFLCALGGVCLQQRSNSGLATYSPPMGPVSERKGSMISVMSSEGNADTPVSKFMDRLLSLMVCNHEKVGLQ IRTNVKDLVGLELSPALYPMLFNKLKNTISKFFDSQGQVLLTDTNTQFVEQTIAIMKNLLDNHTEGSSEHLGQASI ETMMLNLVRYVRVLGNMVHAIQIKTKLCQLVEVMMARRDDLSFCQEMKFRNKMVEYLTDWVMGTSNQAADDDVKCL TRDLDQASMEAVVSLLAGLPLQPEEGDGVELMEAKSQLFLKYFTLFMNLLNDCSEVEDESAQTGGRKRGMSRRLAS LRHCTVLAMSNLLNANVDSGLMHSIGLGYHKDLQTRATFMEVLTKILQQGTEFDTLAETVLADRFERLVELVTMMG DQGELPIAMALANVVPCSQWDELARVLVTLFDSRHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVY GATYLQKLLDPLLRIVITSSDWQHVSFEVDPTRLEPSESLEENQRNLLQMTEKFFHAIISSSSEFPPQLRSVCHCL YQATCHSLLNKATVKEKKENKKSVVSQRFPQNSIGAVGSAMFLRFINPAIVSPYEAGILDKKPPPRIERGLKLMSK ILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSLSFISDGNVLALHRLLWNNQEKIGQ YLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPVADTHWSSLNLTSSKFEEFMTRHQVHEKEEFKALKTLSIFYQA GTSKAGNPIFYYVARRFKTGQINGDLLIYHVLLTLKPYYAKPYEIVVDLTHTGPSNRFKTDFLSKWFVVFPGFAYD NVSAVYIYNCNSWVREYTKYHERLLTGLKGSKRLVFIDCPGKLAEHIEHEQQKLPAATLALEEDLKVFHNALKLAH KDTKVSIKVGSTAVQVTSAERTKVLGQSVFLNDIYYASEIEEICLVDENQFTLTIANQGTPLTFMHQECEAIVQSI IHIRTRWELSQPDSIPQHTKIRPKDVPGTLLNIALLNLGSSDPSLRSAAYNLLCALTCTFNLKIEGQLLETSGLCI PANNTLFIVSISKTLAANEPHLTLEFLEECISGFSKSSIELKHLCLEYMTPWLSNLVRFCKHNDDAKRQRVTAILD KLITMTINEKQMYPSIQAKIWGSLGQITDLLDVVLDSFIKTSATGGLGSIKAEVMADTAVALASGNVKLVSSKVIG RMCKIIDKTCLSPTPTLEQHLMWDDIAILARYMLMLSFNNSLDVAAHLPYLFHVVTFLVATGPLSLRASTHGLVIN IIHSLCTCSQLHFSEETKQVLRLSLTEFSLPKFYLLFGISKVKSAAVIAFRSSYRDRSFSPGSYERETFALTSLET VTEALLEIMEACMRDIPTCKWLDQWTELAQRFAFQYNPSLQPRALVVFGCISKRVSHGQIKQIIRILSKALESCLK GPDTYNSQVLIEATVIALTKLQPLLNKDSPLHKALFWVAVAVLQLDEVNLYSAGTALLEQNLHTLDSLRIFNDKSP EEVFMAIRNPLEWHCKQMDHFVGLNFNSNFNFALVGHLLKGYRHPSPAIVARTVRILHTLLTLVNKHRNCDKFEVN TQSVAYLAALLTVSEEVRSRCSLKHRKSLLLTDISMENVPMDTYPIHHGDPSYRTLKETQPWSSPKGSEGYLAATY PTVGQTSPRARKSMSLDMGQPSQANTKKLLGTRKSFDHLISDTKAPKRQEMESGITTPPKMRRVAETDYEMETQRI SSSQQHPHLRKVSVSESNVLLDEEVLTDPKIQALLLTVLATLVKYTTDEFDQRILYEYLAEASVVFPKVFPVVHNL LDSKINTLLSLCQDPNLLNPIHGIVQSVVYHEESPPQYQTSYLQSFGFNGLWRFAGPFSKQTQIPDYAELIVKFLD ALIDTYLPGIDEETSEESLLTPTSPYPPALQSQLSITANLNLSNSMTSLATSQHSPGIDKENVELSPTTGHCNSGR TRHGSASQVQKQRSAGSFKRNSIKKIV (SEQ ID NO: 13) In another embodiment the EV is loaded with a nucleic acid molecule encoding a polypeptide at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 (shown below). The polypeptide may have GTPase-activation activity. The nucleic acid molecule may be an mRNA or an analogue. DLQTRATFMEVLTKILQQGTEFDTLAETVLADRFERLVELVTMMGDQGELPIAMALANVVPCSQWDELARVLVTLF DSRHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQKLLDPLLRIVITSSDWQHVSFEVDP TRLEPSESLEENQRNLLQMTEKFFHAIISSSSEFPPQLRSVCHCLYQVVSQRFPQNSIGAVGSAMFLRFINPAIVS PYEAGILDKKPPPRIERGLKLMSKILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSL SFISDGNVLALHRLLWNNQEKIGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPVADTHW (SEQ ID NO: 14) The polypeptide encoded by the cargo nucleic acid molecule may comprise a CAAX motif, for instance according to GCMSCKCVLS (SEQ ID NO: 15). This motif may aid with targeting to the plasma membrane. The motif may be positioned at the C-terminus of the polypeptide, for instance the C-terminal end of SEQ ID NO: 14 or variants thereof. Thus, the EV may be loaded with a nucleic acid molecule encoding a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 and comprising SEQ ID NO: 15. In an example, the sequence is SEQ ID NO: 16. DLQTRATFMEVLTKILQQGTEFDTLAETVLADRFERLVELVTMMGDQGELPIAMALANVVPCSQWDELARVLVTLF DSRHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQKLLDPLLRIVITSSDWQHVSFEVDP TRLEPSESLEENQRNLLQMTEKFFHAIISSSSEFPPQLRSVCHCLYQVVSQRFPQNSIGAVGSAMFLRFINPAIVS PYEAGILDKKPPPRIERGLKLMSKILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSL SFISDGNVLALHRLLWNNQEKIGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPVADTHWGCMSCKCVLS (SEQ ID NO: 16) In some embodiments, the nucleic acid cargo comprises a C / D box. For instance, the nucleic acid cargo may be an mRNA or analogue comprising a C / D box. This is particularly relevant where the polypeptide of the first aspect comprises L7Ae, as discussed herein. The C / D box may be gggtaccgtgatccgaaaggtgagtaccc (SEQ ID NO: 17). The cargo may be a nucleic acid molecule, such as an mRNA or an analogue, that comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 19 or 20 (below). The cargo may comprise SEQ ID NO: 19 or 20. The cargo may comprise a C / D box. The cargo may be an mRNA comprising a poly-A tail. GATCTCCAGACAAGAGCTACATTTATGGAAGTTCTGACAAAAATCCTTCAACAAGGCACAGAATTTGACACACTTG CAGAAACAGTATTGGCTGATCGGTTTGAGAGATTGGTGGAACTGGTCACAATGATGGGTGATCAAGGAGAACTCCC TATAGCGATGGCTCTGGCCAATGTGGTTCCTTGTTCTCAGTGGGATGAACTAGCTCGAGTTCTGGTTACTCTGTTT GATTCTCGGCATTTACTCTACCAACTGCTCTGGAACATGTTTTCTAAAGAAGTAGAATTGGCAGACTCCATGCAGA CTCTCTTCCGAGGCAACAGCTTGGCCAGTAAAATAATGACATTCTGTTTCAAGGTATATGGTGCTACCTATCTACA AAAACTCCTGGATCCTTTATTACGAATTGTGATCACATCCTCTGATTGGCAACATGTTAGCTTTGAAGTGGATCCT ACCAGGTTAGAACCATCAGAGAGCCTTGAGGAAAACCAGCGGAACCTCCTTCAGATGACTGAAAAGTTCTTCCATG CCATCATCAGTTCCTCCTCAGAATTCCCCCCTCAACTTCGAAGTGTGTGCCACTGTTTGTACCAGGTGGTTAGCCA GCGTTTCCCTCAGAACAGCATCGGTGCAGTAGGAAGTGCCATGTTCCTCAGATTTATCAATCCTGCCATTGTCTCA CCGTATGAAGCaGGGATTTTAGATAAAAAGCCACCACCTAGAATCGAAAGGGGCTTGAAGTTAATGTCAAAGATAC TTCAGAGTATTGCCAATCATGTTCTCTTCACAAAAGAAGAACATATGCGGCCTTTCAATGATTTTGTGAAAAGCAA CTTTGATGCAGCACGCAGGTTTTTCCTTGATATAGCATCTGATTGTCCTACAAGTGATGCAGTAAATCATAGTCTT TCCTTCATAAGTGACGGCAATGTGCTTGCTTTACATCGTCTACTCTGGAACAATCAGGAGAAAATTGGGCAGTATC TTTCCAGCAACAGGGATCATAAAGCTGTTGGAAGACGACCTTTTGATAAGATGGCAACACTTCTTGCATACCTGGG TCCTCCAGAGCACAAACCTGTGGCAGATACACACTGG (SEQ ID NO: 19) GATCTCCAGACAAGAGCTACATTTATGGAAGTTCTGACAAAAATCCTTCAACAAGGCACAGAATTTGACACACTTG CAGAAACAGTATTGGCTGATCGGTTTGAGAGATTGGTGGAACTGGTCACAATGATGGGTGATCAAGGAGAACTCCC TATAGCGATGGCTCTGGCCAATGTGGTTCCTTGTTCTCAGTGGGATGAACTAGCTCGAGTTCTGGTTACTCTGTTT GATTCTCGGCATTTACTCTACCAACTGCTCTGGAACATGTTTTCTAAAGAAGTAGAATTGGCAGACTCCATGCAGA CTCTCTTCCGAGGCAACAGCTTGGCCAGTAAAATAATGACATTCTGTTTCAAGGTATATGGTGCTACCTATCTACA AAAACTCCTGGATCCTTTATTACGAATTGTGATCACATCCTCTGATTGGCAACATGTTAGCTTTGAAGTGGATCCT ACCAGGTTAGAACCATCAGAGAGCCTTGAGGAAAACCAGCGGAACCTCCTTCAGATGACTGAAAAGTTCTTCCATG CCATCATCAGTTCCTCCTCAGAATTCCCCCCTCAACTTCGAAGTGTGTGCCACTGTTTGTACCAGGTGGTTAGCCA GCGTTTCCCTCAGAACAGCATCGGTGCAGTAGGAAGTGCCATGTTCCTCAGATTTATCAATCCTGCCATTGTCTCA CCGTATGAAGCaGGGATTTTAGATAAAAAGCCACCACCTAGAATCGAAAGGGGCTTGAAGTTAATGTCAAAGATAC TTCAGAGTATTGCCAATCATGTTCTCTTCACAAAAGAAGAACATATGCGGCCTTTCAATGATTTTGTGAAAAGCAA CTTTGATGCAGCACGCAGGTTTTTCCTTGATATAGCATCTGATTGTCCTACAAGTGATGCAGTAAATCATAGTCTT TCCTTCATAAGTGACGGCAATGTGCTTGCTTTACATCGTCTACTCTGGAACAATCAGGAGAAAATTGGGCAGTATC TTTCCAGCAACAGGGATCATAAAGCTGTTGGAAGACGACCTTTTGATAAGATGGCAACACTTCTTGCATACCTGGG TCCTCCAGAGCACAAACCTGTGGCAGATACACACTGGGGCtGCATGAGCTGCAAGTGTGTGCTCTCCTGA (SEQ ID NO: 20) In a fourth aspect, there is provided a method of making an EV of the third aspect. The method may comprise: i) transferring a vector encoding a polypeptide of the first aspect to a cell suitable for producing EVs, and ii) obtaining EVs from said cell. The vector may comprise a nucleic acid of the second aspect. In a particular embodiment, the EVs are human exosomes. The method of the fourth aspect may also comprise transferring cargo to the EV. For instance, the method may comprise transferring mRNA to the EV. The mRNA may be a nucleic acid analogue and may encode a therapeutic agent. The cargo may be any as discussed for the third aspect. Thus, the method may comprise: i) transferring a vector encoding a polypeptide of the first aspect to a cell suitable for producing EVs, ii) obtaining EVs from said cell, and iii) loading cargo into the EVs. The cargo may be encoded by a vector; thus the method may comprise: i) transferring one or more vectors encoding a cargo and a polypeptide of the first aspect to a cell suitable for producing EVs, and ii) obtaining EVs from said cell. The method may also comprise the purification of the EVs. The purification may involve the binding of an agent to a purification moiety. The binding agent may be a binding protein. For instance, the purification may involve the use of an antibody, or antigen-binding fragment thereof, that can specifically bind to the polypeptide of the first aspect. The binding agent may be a natural ligand or receptor for the targeting moiety. The purification may involve the use of a binding agent that can specifically bind to the targeting moiety of the polypeptide of the first aspect. The purification may involve the use of a binding agent that can specifically bind to the purification moiety of the polypeptide of the first aspect. The binding agent may be immobilised to a substrate, such as a bead. Thus, the method may comprise: i) transferring a vector encoding a polypeptide of the first aspect to a cell suitable for producing EVs, ii) obtaining EVs from said cell, and iii) loading cargo into the EVs; iv) purifying the EVs. The purification may comprise the binding of an agent to a purification moiety and the binding of an agent to the targeting moiety. Thus, the purification may enrich the EVs based on the binding of two separate agents. The method may further comprise formulating the EVs into a format suitable for shipping or storage or formulating the EVs into a pharmaceutical composition. In a fifth aspect, there is provided a method of purifying an EV of the third aspect. The method may comprise: i) obtaining a population comprising EVs of the third aspect, ii) contacting the population comprising EVs with a binding agent that can specifically bind to the polypeptide of the first aspect; and iii) isolating EVs bound to said binding agent. The binding agent may specifically bind to the targeting moiety of the polypeptide of the first aspect. The binding agent may specifically bind to the purification moiety of the polypeptide of the first aspect. The binding agent may be immobilised to a substrate, such as a bead. The binding agent may be a binding protein. The binding agent may be an antibody, antigen-binding fragment thereof, or based on an antibody scaffold. The binding agent may be a natural ligand or receptor for the targeting moiety. For instance, the purification may involve the use of an immobilised antibody that can specifically bind to the polypeptide of the first aspect. The purification may involve the use of an immobilised natural binding partner for the targeting moiety. The purification may comprise the binding of an agent to a purification moiety and the binding of an agent to the targeting moiety. Thus, the purification may enrich the EVs based on the binding of two separate agents. The method may further comprise formulating the EVs into a format suitable for shipping or storage or formulating the EVs into a pharmaceutical composition. In a sixth aspect, there is provided a pharmaceutical composition comprising a polypeptide of the first aspect, an EV of the third aspect, or an EV made according to the fourth or fifth aspects. The pharmaceutical composition may comprise a pharmaceutically acceptable vehicle, a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable stabilizer, or a pharmaceutically acceptable preservative, or any combination thereof. To be pharmaceutically acceptable, a substance or combination of substances must be suitable for the formulation of pharmaceutical compositions or a medicament. The pharmaceutical composition may comprise a therapeutically effective amount of the agents of the present disclosure. The phrases “therapeutically effective amount” and “effective amount” and the like, as used herein, indicate an amount necessary to administer to a subject, or to a cell, tissue, or organ of a subject, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect. The effective amount is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician. A pharmaceutical composition of the present disclosure may be formulated for administration to any subject in need thereof. A “subject”, as used herein, may be a vertebrate, mammal, or domestic animal. Most preferably, the subject is a human. The polypeptide of the first aspect and the EV of the third aspect may be used in therapy. Thus, in a seventh aspect, there is provided a polypeptide of the first aspect, an EV of the third aspect, an EV made according to the fourth or fifth aspects, or a pharmaceutical composition of the sixth aspect for use as a medicament. During use, the polypeptide of the first aspect is bound to a therapeutic agent. There is provided a method of treatment comprising administering a therapeutically effective amount of a polypeptide of the first aspect, an EV of the third aspect, an EV made according to the fourth or fifth aspects, or a pharmaceutical composition of the sixth aspect to a subject in need thereof. The polypeptide of the first aspect is bound to a therapeutic agent, and hence a therapeutically effective amount of this polypeptide depends on the therapeutic agent. There is provided use of a polypeptide of the first aspect, an EV of the third aspect, an EV made according to the fourth or fifth aspects, or a pharmaceutical composition of the sixth aspect for the manufacture of a medicament. As discussed herein, the polypeptide may comprise a targeting moiety for Schwann cells, such as a targeting moiety directed to PLAUR, FGFR1, or GALR1. For instance, the polypeptide may comprise galanin. In such embodiments, the polypeptide or EV may be for the treatment of a pathology associated with Schwann cells. The polypeptide or EV may be for the treatment of a Schwann cell tumour. The polypeptide or EV may be for the treatment of a Schwannosis or a Schwannoma. The polypeptide or EV may be for the treatment of Neurofibromatosis type 1 (NF1). The polypeptide or EV may be for the treatment of Charcot-Marie-Tooth disease. The EV may comprise a cargo or therapeutic agent that is relevant to the disease to be treated. For instance, nucleic acid molecules encoding neurofibromin or a portion or variant thereof are described for the third aspect and are particularly relevant to the treatment of NF1. The inventors have identified that there is a need for medicaments that can be used to treatment pathologies associated with Schwann cells. As discussed herein, the inventors have identified that PLAUR, FGFR1, or GALR1 can be used to target EVs to Schwann cells. Thus, in an eighth aspect, there is provided a polypeptide that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent and at least a portion of an EV-associated protein. The binding agent may be any as described below for the tenth aspect. For instance, the binding agent may be an antibody or based on an antibody scaffold. In addition, the binding agent may a peptide capable of binding to GALR1. The peptide may be or may comprise galanin. For instance, the peptide may be the 30 residues of galanin. The peptide may comprise SEQ ID NO: 5 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 5 with no more than 5, 4, 3, 2, 1, or no substitutions. The binding agent may be or comprise SEQ ID NO: 5 and so the polypeptide of the eighth aspect may comprise a binding agent that comprises SEQ ID NO: 5. The binding agent may be a peptide comprising SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 6 with no more than 5, 4, 3, 2, 1, or no substitutions. The binding agent may be or comprise SEQ ID NO: 6 and so the polypeptide of the eighth aspect may comprise a binding agent that comprises SEQ ID NO: 6. The at least a portion of an EV-associated protein is from or derived from a protein that is present in or enriched in EVs. The EV-associated protein may be a protein that is present in or enriched in exosomes. For instance, human exosomes are known to be enriched for certain proteins, and the polypeptide of the eighth aspect may comprise a portion of one of said proteins. Methods of making EVs or exosomes are provided herein, and the EV-associated protein may be any protein that is present in EVs or exosomes produced by said methods. The EV-associated protein may be any protein that is enriched in EVs or exosomes produced by said methods. EV-associated protein may be any protein that is present in more than 50%, 60%, 70%, 80%, 90%, 95%, or 99% EVs or exosomes produced by said methods and which is detectable by flow cytometry. Examples of proteins known to associated with EVs or exosomes are the tetraspanin family. The polypeptide of the eighth aspect may be conjugated or fused to a member of the tetraspanin family. The member of the tetraspanin- family may be any one of CD9, CD37, CD63, CD81, or CD82. Thus, the polypeptide of the eighth aspect may comprise at least a portion, or all, of any one CD9, CD37, CD63, CD81, or CD82. In particular, the polypeptide of the eighth aspect may comprise at least a portion, or all, of CD63. As discussed, the proteins may be matched to a subject intended to be treated, and so the proteins, such as CD63, may be human. In a ninth aspect, there is provided a nucleic acid molecule encoding a polypeptide of the eighth aspect. The nucleic acid may be part of a vector. The vector may include an expression cassette. For instance, a promoter operably linked to the gene encoding the polypeptide of the eighth aspect. In a tenth aspect, there is provided a nanoparticle or an EV that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The binding agent may be present on the outside of the nanoparticle or the EV. The binding agent may therefore be a targeting moiety. The binding agent may be a binding protein, such as an antibody, antigen-binding fragment thereof, or comprise an antibody scaffold. The binding agent may be a single-chain variable fragment (scFv) of an antibody. The binding agent may be a single-domain antibody (sdAb), sometimes known as a nanobody. The binding agent may be a binding protein, such as an antibody (e.g. an sdAb) that is specific for PLAUR, FGFR1, or GALR1. In particular embodiments, the binding agent specifically binds to GALR1. The targeting moiety, when comprised by a nanoparticle or an EV, such as an exosome, may affect the interaction between the nanoparticle / EV and Schwann cells. For instance, the targeting moiety may increase the delivery of cargo to Schwann cells in comparison to otherwise identical nanoparticles / EVs without the targeting moiety. In particular embodiments, the binding agent is a peptide capable of binding to GALR1 (see Example 3). The peptide may be or may comprise galanin. For instance, the peptide may be the 30 residues of galanin. The peptide may comprise SEQ ID NO: 5 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 5 with no more than 5, 4, 3, 2, 1, or no substitutions. The binding agent may be or comprise SEQ ID NO: 5 and so the nanoparticle or EV of the tenth aspect may comprise a binding agent that comprises SEQ ID NO: 5. The binding agent may be a peptide comprising SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions. The peptide may comprise SEQ ID NO: 6 with no more than 5, 4, 3, 2, 1, or no substitutions. The binding agent may be or comprise SEQ ID NO: 6 and so the nanoparticle or EV of the tenth aspect may comprise a binding agent that comprises SEQ ID NO: 6. The binding agent may be fused to a polypeptide or protein comprised by the nanoparticle or EV. Where the binding agent is a polypeptide, the binding agent may be part of a fusion protein or a chimeric protein comprised by the nanoparticle or EV. The fusion protein may comprise a protein or a portion of a protein that is associated with EVs or exosomes. For instance, the fusion protein may comprise a protein or a portion of a protein that is associated with human exosomes. Such proteins may be referred to as EV-associated proteins and are described more fully for the eighth aspect and the first aspect. The binding agent may be part of a polypeptide of the eighth aspect. The binding agent may be displayed on the outside of the nanoparticle or EV. Thus, the binding agent may be positioned on a part of the tetraspanin-family member that is outside of the EV. As discussed in relation to the first aspect, the binding agent may be present in a fusion protein, and may be positioned N-terminally to a portion of a tetraspanin-family protein that is in the “n” topology, for instance because it lacks TM1. Alternatively, the binding agent may be present in or attached to a loop of a tetraspanin-family protein that is present on the outside of the EV. Other ways of displaying peptides and polypeptides on the surfaces of nanoparticles and EVs are known, and any suitable approach may be used to display the binding agent on the outside of the nanoparticle or EV. The nanoparticle or EV may also comprise a purification moiety. The purification moiety may have the features as described for the first aspect. The purification moiety may be a part of the same protein or fusion protein as the binding agent of the tenth aspect or may be part of the different protein or fusion protein. For instance, the purification moiety may be a part of the same polypeptide or a different polypeptide to a galanin peptide. The EV may be a vesicle that is produced by a cell and can be purified, and which can be maintained extracellularly. The cell may be a eukaryotic cell. The cell may be from the same species as the subject for which the EV is intended to treat. Thus, the EV may be a vesicle that is produced by a mammalian cell or by a human cell. The EV may be a vesicle that is released extracellularly, e.g. into the supernatant of a culture, by a cell. The cell may be a eukaryotic cell. The cell may be from the same species as the subject for which the EV is intended to treat. Thus, the EV may be a vesicle that is released extracellularly, e.g. into the supernatant of a culture, by a mammalian cell or a human cell. In particular embodiments, the EV is an exosome. Again, the exosome may be obtained or obtainable from a cell that is of same species as the subject for which the exosome is intended to treat. The cell may be a eukaryotic cell. The exosome may be obtained or obtainable from a mammalian cell or a human cell. The EV may have any features or properties as described for the third aspect. The nanoparticle may be any nanoparticle suitable for being targeted to a cell or tissue by a targeting moiety disclosed herein and which can deliver a cargo to a cell. The nanoparticle may be suitable for drug-delivery to humans. Examples of nanoparticles include liposomes, polymeric nanoparticles, virus-like particles (VLPs), and lipid nanoparticles (LNPs). The nanoparticle may be an LNP. The LNP may comprise an ionisable lipid (e.g. an ionisable cationic lipid or a neutral ionisable amino lipids ), a sterol (e.g. cholesterol), and one or more other types of lipids (e.g. phospholipids and / or PEGylated lipids). The LNPs suitable for the present invention are capable of being targeted by a targeting moiety disclosed herein and which can deliver a cargo (e.g. a nucleic acid) to a cell. Methods of conjugating targeting moieties to LNPs are known in the art. One of the lipids within the LNP may include a conjugation moiety that allows attachment of the targeting moiety. The lipid for conjugation may comprises a linker to which the conjugation moiety is attached. Examples of conjugation moieties include maleimide groups. Methods of conjugating targeting moieties to VLPs are known in the art. For instance, by genetically fusing a polypeptide targeting moiety to a viral coat protein. Alternatively, a targeting moiety may be covalently attached to a viral coat protein or to the VLP after translation or after VLP assembly. The nanoparticle or EV may be loaded with a cargo such as a therapeutic agent. The cargo or therapeutic agent may be a polypeptide or a nucleic acid molecule. The nucleic acid may be suitable for causing a therapeutic change in gene expression in a target cell, for instance by editing the cell’s genome, by reducing expression of a gene or genes in a cell, by inhibiting translation of a specific mRNA or mRNAs in the cell, or by being translated within the cell. The agent may be any cargo discussed for the third aspect. In a particular embodiment, the nanoparticle or EV is loaded with mRNA or an analogue. The cargo may be less than 8.5kb. The cargo may be less than 7kb, 6kb, 5kb, 4kb, or 3kb. The cargo may be less than 1.5kb. The cargo may comprise one or more modified sugar moieties. For instance, the 2’ position of one or more sugar moieties within the nucleic acid cargo may be modified. In addition, the 4’ position may be modified (e.g. locked nucleic acids). The cargo may comprise one or more modified linkages between monomers. The cargo may comprise one or more modified nucleobases. Thus, the cargo may be a nucleic acid analogue. The nucleic acid cargo may encode neurofibromin or a portion or variant thereof. The cargo may be mRNA or an analogue encoding neurofibromin or a portion or variant thereof. The cargo may encode a portion of neurofibromin that retains its function as a GTPase-activating protein. The cargo may encode a hyperactive variant of neurofibromin. The cargo may encode a variant of neurofibromin disclosed in Bai et al. Gen Ther. 2019 Jun; 26 (6) (herein incorporated by reference). The mRNA cargo may be approximately 1 to 1.4, approximately 1.1 to 1.3, or approximately 1.2 kb. The mRNA cargo may be 1.197 kb. In a particular embodiment the nanoparticle or EV is loaded with a nucleic acid molecule encoding SEQ ID NO: 13 or a portion or variant thereof. The portion or variant may be a polypeptide with GTPase-activation activity. The portion or variant may comprise separate regions of SEQ ID NO: 13 fused together. The nanoparticle or EV may be loaded with a nucleic acid molecule encoding a polypeptide at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14. The polypeptide may have GTPase-activation activity. The nucleic acid molecule may be an mRNA or an analogue. The polypeptide encoded by the cargo nucleic acid molecule may comprise a CAAX motif, for instance according to SEQ ID NO: 15. This motif may aid with targeting to the plasma membrane. The motif may be positioned at the C-terminus of the polypeptide, for instance the C-terminal end of SEQ ID NO: 14 or variants thereof. Thus, the nanoparticle or EV may be loaded with a nucleic acid molecule encoding a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 and comprising SEQ ID NO: 15. In an example, the sequence is SEQ ID NO: 16. In some embodiments, the nucleic acid cargo comprises a C / D box. For instance, the nucleic acid cargo may be an mRNA or analogue comprising a C / D box. This is particularly relevant where the nanoparticle or EV comprises L7Ae, as discussed herein. The C / D box may be SEQ ID NO: 17. The cargo may be a nucleic acid molecule, such as an mRNA or an analogue, that comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 19 or 20. The cargo may comprise SEQ ID NO: 19 or 20. The cargo may be an mRNA comprising a poly-A tail. The cargo or therapeutic agent may be present inside the nanoparticle or EV. The cargo or therapeutic agent may be present inside the EV and in solution. The cargo or therapeutic agent may be in association with a protein or nucleic acid that is, itself, in association with the EV. For instance, the EV may comprise a polypeptide with a cargo-binding domain and the cargo or therapeutic agent may be bound by the cargo-binding domain. For instance, the EV may comprise a polypeptide with a nucleic-acid-binding domain and a therapeutic nucleic acid molecule may be bound by the nucleic-acid-binding domain. The EV comprise a polypeptide with a nucleic-acid-binding domain inside the EV, and the therapeutic nucleic acid molecule may be bound by the nucleic-acid-binding domain. In particular embodiments, the EV of the tenth aspect comprises a polypeptide of the first aspect. In certain embodiments, the EV of the tenth aspect comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions, wherein the peptide is external to the EV, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In further embodiments, the EV of the tenth aspect comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 5, 4, 3, 2, 1, or no substitutions, wherein the peptide is external to the EV, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In an embodiment, the EV of the tenth aspect is an exosome that comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions, wherein the peptide is external to the exosome, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In a further embodiment, the EV of the tenth aspect is an exosome that comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 5, 4, 3, 2, 1, or no substitutions, wherein the peptide is external to the exosome, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In an embodiment, the nanoparticle of the tenth aspect is an LNP that comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions, wherein the peptide is external to the LNP, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In a further embodiment, the nanoparticle of the tenth aspect is an LNP that comprises: a peptide that is SEQ ID NO: 5 or SEQ ID NO: 6, with no more than 5, 4, 3, 2, 1, or no substitutions, wherein the peptide is external to the LNP, and a nucleic acid encoding a portion of neurofibromin that has GTPase activity. In an eleventh aspect, there is provided a method of making a nanoparticle or an EV of the tenth aspect. The method may comprise: i) transferring a vector encoding a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs; and ii) obtaining EVs from said cell. The vector may encode a galanin peptide as discussed for the eighth or tenth aspect. The galanin peptide may be part of a fusion protein as discussed for the eighth or tenth aspect. The fusion protein is present in EVs produced by cell and may be enriched or traffic to said EVs. The fusion protein may comprise a portion of a tetraspanin- family protein as discussed herein. For instance, the fusion protein may comprise a CD63 protein or portion thereof. In a particular embodiment, the EVs are human exosomes. The EVs may have any features or properties as discussed for the tenth aspect. The method of the eleventh aspect may also comprise transferring cargo to the EV. For instance, the method may comprise transferring mRNA to the EV. The mRNA may be a nucleic acid analogue and may encode a therapeutic agent. In particular, the mRNA may encode neurofibromin or a portion or variant thereof as discussed for the tenth aspect. The cargo may be any as discussed for the tenth aspect. Thus, the method may comprise: i) transferring a vector encoding a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs; ii) obtaining EVs from said cell; and iii) loading cargo into the EVs. The cargo may be encoded by a vector; thus the method may comprise: i) transferring one or more vectors encoding a cargo and a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs, and ii) obtaining EVs from said cell. The method may also comprise the purification of the EVs. The purification may involve the binding of an agent to a purification moiety and / or to the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The binding agent for purification may be a binding protein. For instance, the purification may involve the use of an antibody, or antigen-binding fragment thereof. The binding agent for purification may be a natural ligand or receptor for the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The purification may involve the use of a binding agent for purification that can specifically bind to a fusion protein comprising the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The purification may involve the use of a binding agent for purification that can specifically bind to a purification moiety present in the EV. The binding agent for purification may be immobilised to a substrate, such as a bead. Thus, the method may comprise: i) transferring a vector encoding a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs; ii) obtaining EVs from said cell; iii) loading cargo into the EVs; and iv) purifying the EVs. The purification may comprise the binding of an agent to a purification moiety and the binding of an agent to the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. Thus, the purification may enrich the EVs based on the binding of two separate agents. The method may further comprise formulating the EVs into a format suitable for shipping or storage or formulating the EVs into a pharmaceutical composition. In a twelfth aspect, there is provided a method of purifying a nanoparticle or an EV of the tenth aspect. The method may comprise: i) obtaining a population comprising EVs of the tenth aspect, ii) contacting the population comprising EVs with a purification binding agent that can specifically bind to the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent or can specifically bind to a purification moiety; and iii) isolating EVs bound to said purification binding agent. The purification binding agent may be a binding protein. For instance, the purification binding agent may be an antibody, or antigen-binding fragment thereof. The purification binding agent may be a natural ligand or receptor for the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The purification binding agent may specifically bind to a fusion protein comprising the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent. The purification binding agent may specifically bind to a purification moiety present in the EV. The purification binding agent may be immobilised to a substrate, such as a bead. The method may further comprise formulating the EVs into a format suitable for shipping or storage or formulating the EVs into a pharmaceutical composition. In a thirteenth aspect, there is provided a pharmaceutical composition comprising a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, or a nanoparticle or an EV made according to the eleventh or twelfth aspects. The pharmaceutical composition may comprise a pharmaceutically acceptable vehicle, a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable stabilizer, or a pharmaceutically acceptable preservative, or any combination thereof. To be pharmaceutically acceptable, a substance or combination of substances must be suitable for the formulation of pharmaceutical compositions or a medicament. The pharmaceutical composition may comprise a therapeutically effective amount of the agents of the present disclosure. The effective amount is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician. A pharmaceutical composition of the present disclosure may be formulated for administration to any subject in need thereof. A “subject”, as used herein, may be a vertebrate, mammal, or domestic animal. Most preferably, the subject is a human. The inventors provide herein approaches to deliver RNA therapeutics to non-targetable cells such as Schwann cells, to treat uncurable pathologies such as Neurofibromatosis type 1 (NF1). In particular, they optimise mRNA delivery and targeting of a GTPase to tumorigenic Schwann cells. Thus, in a fourteenth aspect, there is provided a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, a nanoparticle or an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use as a medicament. There is provided a method of treatment comprising administering a therapeutically effective amount of a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, a nanoparticle or an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect to a subject in need thereof. There is provided use of a polypeptide of the eighth aspect, a nanoparticle or an EV of the tenth aspect, a nanoparticle or an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for the manufacture of a medicament. In embodiments of the fourteenth aspect, the nanoparticles or EVs comprise therapeutic agents. As discussed herein, the nanoparticle or EV comprises a targeting moiety for Schwann cells, such as a targeting moiety directed to PLAUR, FGFR1, or GALR1. For instance, the targeting moiety may comprise a polypeptide that comprises galanin or a variant thereof, as discussed for the eighth or tenth aspect. Thus, the nanoparticle or EV may be for the treatment of a pathology associated with Schwann cells. The nanoparticle or EV may be for the treatment of a Schwann cell tumour. The nanoparticle or EV may be for the treatment of Schwannosis or a Schwannoma. The nanoparticle or EV may be for the treatment of Neurofibromatosis type 1 (NF1). The nanoparticle or EV may be for the treatment of Charcot-Marie-Tooth disease. As discussed for the tenth aspect, the nanoparticle or EV may comprise a nucleic acid cargo, such as an mRNA, that encodes neurofibromin or a portion or variant thereof. The cargo may encode SEQ ID NO: 13 or a portion or variant thereof. The cargo may encode a portion of neurofibromin that retains its function as a GTPase-activating protein. The cargo may encode a hyperactive variant of neurofibromin. The cargo may encode a polypeptide at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14. The cargo may comprise SEQ ID NO: 15, for instance at the C-terminus. The cargo may encode a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 and comprising SEQ ID NO: 15 (for instance, SEQ ID NO: 16). The cargo may comprise a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 19 or 20. The cargo may comprise a poly-A tail. The mRNA cargo may be approximately 1 to 1.4, approximately 1.1 to 1.3, or approximately 1.2 kb. The mRNA cargo may be 1.197 kb. These embodiments are particularly relevant to the treatment of NF1. Thus, in a certain embodiment, there is provided an EV of the tenth aspect, an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use in a method of treating NF1, wherein the EV comprises a nucleic acid cargo that encodes neurofibromin or a portion or variant thereof. In another embodiment, there is provided an LNP of the tenth aspect, an LNP made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use in a method of treating NF1, wherein the LNP comprises a nucleic acid cargo that encodes neurofibromin or a portion or variant thereof. In another embodiment, there is provided an EV of the tenth aspect, an EV made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use in a method of treating NF1, wherein the EV comprises an nucleic acid cargo that encodes neurofibromin or a portion or variant thereof and the EV displays a galanin peptide as disclosed herein on the outside of the EV. In another embodiment, there is provided a human exosome of the tenth aspect, a human exosome made according to the eleventh or twelfth aspects, or a pharmaceutical composition comprising a human exosome of the thirteenth aspect for use in a method of treating NF1, wherein the exosome comprises an mRNA cargo that encodes neurofibromin or a portion or variant thereof and the exosome displays a galanin peptide as disclosed herein on the outside of the exosome. In another embodiment, there is provided an LNP of the tenth aspect, an LNP made according to the eleventh or twelfth aspects, or a pharmaceutical composition of the thirteenth aspect for use in a method of treating NF1, wherein the LNP comprises a nucleic acid cargo that encodes neurofibromin or a portion or variant thereof and the LNP displays a galanin peptide as disclosed herein on the outside of the LNP. The medicaments of the present disclosure, whether described for the seventh or the fourteenth aspect, may be administered to a subject by any suitable means and in any suitable form. Suitable means for administering LNPs and EVs, such as exosomes, are known in the art. A suitable dosing regimen may be used depending on the organism to be treated. It will be appreciated that medicaments of the present disclosure may be used in a monotherapy. Alternatively, medicaments of the present disclosure may be used as an adjunct to, or in combination with, known therapies. The medicaments of the present disclosure may be for administration before, during or after onset of the pathological condition. The medicaments of the present disclosure, whether described for the seventh or the fourteenth aspect, may be for the treatment of any subject in need thereof. The medicaments may be for the treatment of a vertebrate, mammal, or domestic animal. Most preferably, the treatment is for a human. The terms “treat”, “treating”, “treatment” and the like, as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the process of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition and includes the administration of any of the medicaments, pharmaceutical compositions, or dosage forms described herein, to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder. For example, treatment is curative or ameliorating. As used herein, “preventing” means preventing in whole or in part, or ameliorating or controlling, or reducing or halting the production or occurrence of the thing or event, for example, the disease, disorder or condition, to be prevented. The terms “administering”, “administer”, “administration” and the like, as used herein, refer to any mode of transferring, delivering, introducing, or transporting a therapeutic agent to a subject in need of treatment with such an agent. The terms “specifically bind” and “specifically binding” are terms of the art. For instance, an antibody is said to specifically bind to a target when it can bind the target but an isotype control (e.g. an otherwise identical antibody with different complementarity determining regions) does not bind. Sequence comparisons can be conducted with the aid of readily available sequence comparison programs. These publicly and commercially available computer programs can calculate sequence identity between two or more sequences. The skilled technician will appreciate how to calculate the percentage identity between two nucleic sequences or two amino acid sequences. In order to calculate the percentage identity, an alignment of the two sequences must first be prepared, followed by calculation of the sequence identity value. The percentage identity for two sequences may take different values depending on: (i) the method used to align the sequences, for example, the Needleman-Wunsch algorithm (e.g. as applied by Needle(EMBOSS) or Stretcher(EMBOSS), the Smith- Waterman algorithm (e.g. as applied by Water(EMBOSS)), or the LALIGN application (e.g. as applied by Matcher(EMBOSS); and (ii) the parameters used by the alignment method, for example, local versus global alignment, the matrix used, and the parameters applied to gaps. In a particular embodiment, the sequence identities disclosed herein may be calculated based on a global alignment of the relevant feature, for instance the comparison of a complete length of a polypeptide or particular feature or domain within the polypeptide to the complete reference sequence recited herein. For example, a claimed portion of a tetraspanin-family protein may be of the recited level of sequence identity when compared to the complete length of the reference sequence for the portion of a tetraspanin-family protein. The same approach may be used of the cargo-binding domain and other domains or features discussed herein. Having made the alignment, there are many different ways of calculating percentage identity between the two sequences. For example, one may divide the number of identities by: (i) the length of shortest sequence; (ii) the length of alignment; (iii) the mean length of sequence; (iv) the number of non-gap positions; or (iv) the number of equivalenced positions excluding overhangs. Furthermore, it will be appreciated that percentage identity is also strongly length-dependent. Therefore, the shorter a pair of sequences is, the higher the sequence identity one may expect to occur by chance. A calculation of percentage identities between two nucleic acid sequences may then be calculated from such an alignment as (N / T)*100, where N is the number of positions at which the sequences share an identical residue, and T is the total number of positions compared including gaps but excluding overhangs. The sequence alignment may be a pairwise sequence alignment. Suitable services include Needle (EMBOSS), Stretcher (EMBOSS), Water (EMBOSS), Matcher (EMBOSS), LALIGN, or GeneWise. In an example, the identity between two amino acid sequences may be calculated using the service Needle(EMBOSS) set to the default parameters, e.g. matrix (BLOSUM62), gap open (10), gap extend (0.5), end gap penalty (false), end gap open (10), and end gap extend (0.5). In another example, the identity between two amino acid sequences may be calculated using the service Matcher (EMBOSS) set to the default parameters, e.g. matrix (BLOSUM62), gap open (14), gap extend (4), alternative matches (1). In an example, the identity between two nucleic acid sequences may be calculated using the service Needle(EMBOSS) set to the default parameters, e.g. matrix (DNAfull), gap open (10), gap extend (0.5), end gap penalty (false), end gap open (10), and end gap extend (0.5). In another example, the identity between two nucleic acid sequences may be calculated using the service Matcher (EMBOSS) set to the default parameters, e.g. matrix (DNAfull), gap open (16), gap extend (4), alternative matches (1). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All of the features described herein (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made to the Examples, which are not intended to limit the invention in any way. EXAMPLES Summary Extracellular vesicles (EV) are important players in cell and tissue crosstalk, through their ability to carry different cargoes such as nucleic acids, proteins or metabolites. Exosomes are a subclass of EV which are typically 40-160nm in diameter which are emerging as interesting diagnostic markers, and delivery vectors. Recent papers have leveraged on the characterisation of several proteins embedded in the exosomal membrane to develop exosomes targeting specific cells and / or loading cargoes such as RNAi, plasmid DNA or mRNA. However, these properties rely on the expression of targeting ligands in the external surface of the exosomes, and independently, RNA-binding proteins in the intralumenal part of the exosomal membrane. These approaches are typically associated with heterogenous populations of exosomes, restricting their potential therapeutic use. In addition, exosomes have been typically targeted to central nervous system, but other cellular targets have not been extensively explored. Here we develop a chimeric protein that combines cell targeting, mRNA loading and purification properties, overcoming some of the technical limitations of exosomes. In addition, we explore different ligands, aimed to target Schwann cells, that are relevant to Schwannosis such as Neurofibromatosis type 1 and other genetic conditions related to Schwann cells such as Charcot Marie Tooth. Example 1 – Design of a chimeric trispanin with RNA-loading activity. Tetraspanins are a family of proteins encompassing four transmembrane domains. CD9, CD37, CD63, CD81 and CD82 are tetraspanins, usually identified as components of the exosomal membrane. Based on structural properties of EV tetraspanins (Curley et al., 2020), the intralumenal carboxyterminal domain of CD63 has been used to create a fusion protein with L7Ae, a protein with binding activity to the C / Dbox mRNA structures (Kojima et al., 2018). However, this approach creates exosomes without a cell-targeting capability. For this reason, additional targeting proteins can be coexpressed, such as RVG-Lamp2b, which was reported to target exosomes to the brain by binding to nicotinic acetylcholine receptor (CHRNA7)[25, 26; Kojima, R., et al. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat Commun 9, 1305 (2018). https: / / doi.org / 10.1038 / s41467-018-03733-8). While this approach has been shown to deliver the cargo mRNA to neurons in vitro and in vivo, the requirement of several proteins, increased the complexity and the heterogeneity of the exosomes, limiting their efficiency and their potential to be translated into clinic. In order to overcome this limitation, we leveraged on the topology of tetraspanins, consisting of four transmembrane domains (TM1 to TM4), providing an ‘M’ conformation, with both amino- and carboxy-terminal domains facing the intraluminal side of the exosomal membrane (Figure 1A, left). Importantly, while, this distribution seems to be conserved across the main tetraspanins located in exosomes (Figure 1B), biochemical studies have suggested that TM1 is not required for the localization of CD63 in exosomes (Curley et al., 2020). According to this model, upon deletion of the TM1 domain, tetraspanins could adopt an ‘n’ configuration, with the N-terminal domain, facing towards the external side of the exosomal membrane, and the carboxy-terminal domain facing inwards (Figure 1A, right). A chimeric construct was designed (Figure 1C, top) to express a protein possessing dual targeting and RNA loading potential. The aim of this strategy is to increase the efficiency of EV targeting and RNA loading whilst decreasing EV heterogeneity as previously described. This approach, based on the development of novel chimeric proteins was named Trispanin RNA targeting and loading exosome (T-REX). These constructs consist of an external domain for targeting ligands and FLAG-tag for exosomal tracking and / or purification. A truncated CD63 trispanin resulting in a nCD63 topology and an intraluminal domain containing the L7Ae protein, as described in Kojima et al., 2018, for the exosomal loading of C / Dbox -containing mRNAs (Figure 1C, bottom). A protein structure model for T-REX was produced with Meta AI software, suggesting that this chimeric protein could fold as expected, providing three transmembrane domains and the N-terminal and C-terminal domains facing outwards and inwards, respectively (Figure 1D). Example 2 – T-REX chimeric protein is expressed and loads mRNA into exosomes. Cells held in suspension require constant shaking and an increase in shear stress has been shown to increase EV production (Patel et al., 2019). Another benefit of these cells is that they can be cultured at a higher cell density and thus more EVs per mL of conditioned media will be produced. For these reasons, HEK293F cells were used and transfected with T-REX plasmid using PEI reagent. Western-blot analysis showed that nCD63 (lacking TM1) is expressed to similar levels as compared with native ‘M’ CD63. Moreover, adding a ligand in the N-terminal region does not interfere with normal expression of the T-REX chimeric protein (Figure 2A). Next, we tested if T-REX was able to load C / D box -containing mRNAs into exosomes, and the impact of mRNA length in loading efficiency. For this reason, mRNAs of three different lengths (0.5, 1, and 8.5 kilobases) were tested (Figure 2B). Exosome purification followed by RNA isolation and qPCR confirmed that T-REX is able to efficiently load mRNA into the exosomes, and efficiency declines with length of the mRNA transcript (Figure 2C). Moreover, Nanoparticle Tracking Analysis (NTA) confirmed that exosomes could be produced using this method and mRNA length does not significantly impact EV size (Figure 2D). Next, we confirmed whether N-terminal fusion motifs could influence exosome production and / or mRNA loading. To this aim, T-REX was used either with no N-terminal ligand, or with ligands ranging from 7.7 to 37.6 KDa, and compared with native ‘M’ CD63 (Figure 2E). Further exosome purification and mRNA analysis showed that these ligands did not significantly affect mRNA loading into exosomes (Figure 2F). Example 3 – T-REX targeting galanin receptor deliver cargo into tumorigenic Schwann cells. Analysis of a human cutaneous neurofibroma scRNAseq dataset revealed significant enrichment of different targeting receptors in Schwann cells (Brosseau et al., 2021). Figure 3A-B shows the presence of Schwann cells in these neurofibromas in cluster 6. Figure 3C highlights the specific expression of targetable receptors within the Schwann cell population, including Plasminogen activator urokinase receptor (PLAUR), Fibroblast growth factor receptor 1 (FGFR1) and in particular, Galanin receptor (GALR1). This information has been used to design and clone three different targeting ligands to T-REX. The targeting ligands are fused to the CD63-L7Ae moiety at the N-terminus. Galanin receptor was selected as 1) its expression seems to be restricted to tumorogenic Schwann cells within a neurofibroma, and 2) amino acids 1 to 30 have been reported to target the receptor. First, we generated immortalised Schwann cells overexpressing GALR1 or control cells (Figure 3D). Efficient overexpression of the receptor was confirmed by qPCR analysis (Figure 3D). Next, we produced exosomes from cells transfected with T- REX with Galanin 1-30 aminoacids fused to the N-terminal domain and nanoluc containing a C / Dbox. Schwann cells were treated with 1xe6exosomes and Following EV treatment, a luciferase assay will be carried out on the cells. This experiment showed that galanin targeting increases luciferase signal in cells expressing GALR1, compared to control cells, confirming receptor-mediated uptake of exosomal nano luciferase mRNA cargo (Figure 3E). Interestingly head to tail inversion of galanin 1-30 ligand still retained activation properties (Figure 3E, right). Methods for examples Plasmids Plasmids P462, P465 as described in Kojima et al., 2018. GRD-C10 construct was generated by gene synthesis based on the sequences described by Bai et al. Gen Ther.2019 Jun; 26 (6) and cloned into the P462 plasmid. NF1 construct was codon optimized and generated by gene synthesis and cloned into the P462 plasmid. T-REX plasmid was generated by replacing CD63 in P465 plasmid, by a fragment produced by gene synthesis containing a cloning site, a FLAG and 47-240 aa of CD63. The sequence of the 2HA-GRD-C10 loading plasmid is below. The open reading frame is in capital letters. The plasmid includes, in order, two HA epitopes, a variant of neurofibromin (encoding SEQ ID NO: 14 – discussed herein), a CAAX motif, a C / D Box, a 6xHis, and a bGH poly (A). gacggatcgggagatctcccgatcccctatggtgcactctcagtacaatctgctctgatgccgcatagttaagcca gtatctgctccctgcttgtgtgttggaggtcgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaaggc ttgaccgacaattgcatgaagaatctgcttagggttaggcgttttgcgctgcttcgcgatgtacgggccagatata cgcgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatgga gttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaata atgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactg cccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgc ctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctatt accatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctcc accccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgc cccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctctctggctaactagagaa cccactgcttactggcttatcgaaattaatacgactcactatagggagacccaagctggctagcgtttaaacttaa gcttgccaccATGGCGTATCCCTATGATGTGCCAGACTATGCTGGCTATCCATATGATGTTCCTGATTATGCTGAT CTCCAGACAAGAGCTACATTTATGGAAGTTCTGACAAAAATCCTTCAACAAGGCACAGAATTTGACACACTTGCAG AAACAGTATTGGCTGATCGGTTTGAGAGATTGGTGGAACTGGTCACAATGATGGGTGATCAAGGAGAACTCCCTAT AGCGATGGCTCTGGCCAATGTGGTTCCTTGTTCTCAGTGGGATGAACTAGCTCGAGTTCTGGTTACTCTGTTTGAT TCTCGGCATTTACTCTACCAACTGCTCTGGAACATGTTTTCTAAAGAAGTAGAATTGGCAGACTCCATGCAGACTC TCTTCCGAGGCAACAGCTTGGCCAGTAAAATAATGACATTCTGTTTCAAGGTATATGGTGCTACCTATCTACAAAA ACTCCTGGATCCTTTATTACGAATTGTGATCACATCCTCTGATTGGCAACATGTTAGCTTTGAAGTGGATCCTACC AGGTTAGAACCATCAGAGAGCCTTGAGGAAAACCAGCGGAACCTCCTTCAGATGACTGAAAAGTTCTTCCATGCCA TCATCAGTTCCTCCTCAGAATTCCCCCCTCAACTTCGAAGTGTGTGCCACTGTTTGTACCAGGTGGTTAGCCAGCG TTTCCCTCAGAACAGCATCGGTGCAGTAGGAAGTGCCATGTTCCTCAGATTTATCAATCCTGCCATTGTCTCACCG TATGAAGCaGGGATTTTAGATAAAAAGCCACCACCTAGAATCGAAAGGGGCTTGAAGTTAATGTCAAAGATACTTC AGAGTATTGCCAATCATGTTCTCTTCACAAAAGAAGAACATATGCGGCCTTTCAATGATTTTGTGAAAAGCAACTT TGATGCAGCACGCAGGTTTTTCCTTGATATAGCATCTGATTGTCCTACAAGTGATGCAGTAAATCATAGTCTTTCC TTCATAAGTGACGGCAATGTGCTTGCTTTACATCGTCTACTCTGGAACAATCAGGAGAAAATTGGGCAGTATCTTT CCAGCAACAGGGATCATAAAGCTGTTGGAAGACGACCTTTTGATAAGATGGCAACACTTCTTGCATACCTGGGTCC TCCAGAGCACAAACCTGTGGCAGATACACACTGGGGCtGCATGAGCTGCAAGTGTGTGCTCTCCTGAtctagatgc aaaatagactttagagggtaccgtgatccgaaaggtgagtaccctgcaacctcgacttcgaactcgagaccggtca tcatcaccatcaccattgagtttaaacccgctgatcagcctcgactgtgccttctagttgccagccatctgttgtt tgcccctcccccgtgccttccttgaccctggaaggtgccactcccactgtcctttcctaataaaatgaggaaattg catcgcattgtctgagtaggtgtcattctattctggggggtggggtggggcaggacagcaagggggaggattggga agacaatagcaggcatgctggggatgcggtgggctctatggcttctgaggcggaaagaaccagctggggctctagg gggtatccccacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctacac ttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggctttccccgtca agctctaaatcgggggctccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaacttgattag ggtgatggttcacgtagtgggccatcgccctgatagacggtttttcgccctttgacgttggagtccacgttcttta atagtggactcttgttccaaactggaacaacactcaaccctatctcggtctattcttttgatttataagggatttt gccgatttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaattaattctgtggaatgtgt gtcagttagggtgtggaaagtccccaggctccccagcaggcagaagtatgcaaagcatgcatctcaattagtcagc aaccaggtgtggaaagtccccaggctccccagcaggcagaagtatgcaaagcatgcatctcaattagtcagcaacc atagtcccgcccctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgccccatggctgac taattttttttatttatgcagaggccgaggccgcctctgcctctgagctattccagaagtagtgaggaggcttttt tggaggcctaggcttttgcaaaaagctcccgggagcttgtatatccattttcggatctgatcagcacgtgttgaca attaatcatcggcatagtatatcggcatagtataatacgacaaggtgaggaactaaaccatggccaagttgaccag tgccgttccggtgctcaccgcgcgcgacgtcgccggagcggtcgagttctggaccgaccggctcgggttctcccgg gacttcgtggaggacgacttcgccggtgtggtccgggacgacgtgaccctgttcatcagcgcggtccaggaccagg tggtgccggacaacaccctggcctgggtgtgggtgcgcggcctggacgagctgtacgccgagtggtcggaggtcgt gtccacgaacttccgggacgcctccgggccggccatgaccgagatcggcgagcagccgtgggggcgggagttcgcc ctgcgcgacccggccggcaactgcgtgcacttcgtggccgaggagcaggactgacacgtgctacgagatttcgatt ccaccgccgccttctatgaaaggttgggcttcggaatcgttttccgggacgccggctggatgatcctccagcgcgg ggatctcatgctggagttcttcgcccaccccaacttgtttattgcagcttataatggttacaaataaagcaatagc atcacaaatttcacaaataaagcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctt atcatgtctgtataccgtcgacctctagctagagcttggcgtaatcatggtcatagctgtttcctgtgtgaaattg ttatccgctcacaattccacacaacatacgagccggaagcataaagtgtaaagcctggggtgcctaatgagtgagc taactcacattaattgcgttgcgctcactgcccgctttccagtcgggaaacctgtcgtgccagctgcattaatgaa tcggccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgctcactgactcgctgcgctc ggtcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccacagaatcaggggataac gcaggaaagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttcc ataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactata aagataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctg tccgcctttctcccttcgggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcg ttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtct tgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggtat gtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggtatctgcg ctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcgg tggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacg gggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacct agatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttacca atgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtg tagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcaccgg ctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctc catccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgcc attgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagctccggttcccaacgatcaaggc gagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctccgatcgttgtcagaagtaagtt ggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgtcatgccatccgtaagatgcttt tctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccggcgt caatacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaa actctcaaggatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatct tttactttcaccagcgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacac ggaaatgttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcgg atacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgac gtc (SEQ ID NO: 18) Cell culture in suspension and exosome production HEK293F cells were seeded in a 500mL shake flasks at a density of 1e6cells / mL. The media used for these cells is Gibco FreeStyle 293 medium. HEK293F cells were seeded in a 500mL shake flasks. A total of 1.5e8cells in a total volume of 50mL Gibco FreeStyle 293 medium. Prior to transfection, the cells were spun down in a centrifuge at 1200 x rpm for 10 minutes at room temperature. The cells were resuspended at a cell total of 1.5e8cells per condition in a volume of 50mL, this was placed into a 500mL shake flask.4 pg / cell of DNA was used, and PEI Max used at a final concentration of 9ug / mL. For the addition of the DNA and PEI, the amounts were diluted in fresh media to a final concentration of 0.5ug / uL. The plasmid and PEI dilutions were incubated at room temperature for 5 mins before they were mixed and incubated for 20 mins. After addition the flask was swirled and placed back in the shaking incubator at 130rpm. 24 hours after transfection, the cells were diluted 1:1 with fresh pre warmed media supplemented with valproic acid at a final concentration of 2.2 mM. A stock solution of valproic acid was produced in water at 220 mM and therefore 10 uL of VPA was added to the media per 1 mL of final transfection volume. The cells were spun down in 50mL falcon tubes, these tubes were spun for 10 mins at 700 x g. The supernatant was poured off into a new 50ml falcon tube and spun for 20 mins at 4000 x g and again the supernatant was poured off into a new 50mL falcon tube. The supernatant was then filtered through a 0.45 µm filter and a 0.22 µm filter PES membrane vacuum unit. The media was concentrated using an Amicon® Ultra-15 Centrifugal Filter Unit (100 KDa) the samples were spun for 15 minutes at 4000 x g. The concentrated samples were added to Ultra-Clear centrifuge tubes and added to the appropriate SW 41 Ti tubes. The SW 41 Ti rotor was placed within the Optima L-90 XP ultracentrifuge and the tubes were spun at 100000 x g (24200 rpm) for 90 mins at 4°C. After centrifugation, the supernatant was removed, and PBS was added to the tubes. These were then spun again at 100000 x g (24200 rpm) for 90 mins at 4°C. The supernatant was removed from the tubes and the pellet was resuspended in 100uL of sterile PBS. The samples were frozen at -80°C. Exosome Quantification - NTA Exosome samples were quantified using the NTA ZetaView (Particle Metrix). The machine is loaded and then calibrated using the NTA beads which were diluted 1:250,000 in filtered H2O. Samples were then run by diluting the exosome sample in filtered PBS to an appropriate dilution to be within the calibration range. Schwann cell culture Inmortalised Schwann cells were obtained from ATCC and cultured in DMEM-10% FBS with Pen / Strep. Single Cell RNA sequencing analysis Publicly available dataset GSE163028, were reanalysed with xxx software. RNA isolation and analysis Exosomes were isolated and RNA was extracted with RNAeasy nano kit column (Qiagen) following the manufacturer instructions. cDNA was produced with high capacity cDNA reverse transcriptase kit (Applied biosystems). mRNA loading was evaluated by qPCR with Master mix fast (Applied biosystems) with the appropriate primers for the target mRNA and the housekeeping gene. References Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol.2011 Apr;29(4):341-5. doi: 10.1038 / nbt.1807. Epub 2011 Mar 20. PMID: 21423189. Aslan C, Kiaie SH, Zolbanin NM, Lotfinejad P, Ramezani R, Kashanchi F, Jafari R. Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope. BMC Biotechnol.2021 Mar 10;21(1):20. doi: 10.1186 / s12896-021-00683-w. PMID: 33691652; PMCID: PMC7945253. Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol.2009 Jul;61(1):1-14; quiz 15-6. doi: 10.1016 / j.jaad.2008.12.051. PMID: 19539839; PMCID: PMC2716546. Brosseau JP, Sathe AA, Wang Y, Nguyen T, Glass DA 2nd, Xing C, Le LQ. Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing. Acta Neuropathol Commun.2021 Jan 7;9(1):11. doi: 10.1186 / s40478-020-01103-4. PMID: 33413690; PMCID: PMC7792184. Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, An YA, Sadek HA, Gordillo R, Akgul Y, Chen S, Samovski D, Fischer-Posovszky P, Kusminski CM, Klein S, Scherer PE. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab.2021 Sep 7;33(9):1853- 1868.e11. doi: 10.1016 / j.cmet.2021.08.002. 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Claims

CLAIMS 1. A polypeptide comprising: a targeting moiety, and a portion of a tetraspanin-family protein, wherein the tetraspanin-family protein is an EV-associated protein, and wherein the polypeptide does not comprise the N-terminal domain of the tetraspanin-family protein and does not comprise TM1 of the tetraspanin-family protein.

2. The polypeptide of claim 1, wherein the tetraspanin-family protein is CD9, CD37, CD63, CD81, or CD82.

3. The polypeptide of claim 1 or claim 2, wherein the portion of a tetraspanin-family protein is a trispanin polypeptide and / or comprises TM2, TM3, and TM4.

4. The polypeptide of any preceding claim, wherein the portion of a tetraspanin-family protein can adopt the “n” topology in a membrane.

5. The polypeptide of any preceding claim, wherein the tetraspanin-family protein is CD63 and the polypeptide does not comprise residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-51 of SEQ ID NO:

1.

6. The polypeptide of any preceding claim, wherein the tetraspanin-family protein is CD63 and the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO:

2.

7. The polypeptide of any preceding claim, wherein the tetraspanin-family protein is CD63 and the portion of CD63 comprises or is a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 3 or 4.

8. The polypeptide of any of claims 1 to 4, wherein the tetraspanin-family protein is CD9 and: the polypeptide does not comprise residues 1-33, 1-35, 1-40, 1-45, 1-50, or 1-55 of SEQ ID NO: 21; and / or the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 25; and / or the portion of CD9 comprises or is a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 26 or 27.

9. The polypeptide of any of claims 1 to 4, wherein the tetraspanin-family protein is CD37 and: the polypeptide does not comprise residues 1-38, 1-40, 1-45, 1-48, 1-50, 1-55, or 1-59 of SEQ ID NO: 22; and / or the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 28; and / or the portion of CD9 comprises or is a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 29 or 30.

10. The polypeptide of any of claims 1 to 4, wherein the tetraspanin-family protein is CD81 and: the polypeptide does not comprise residues 1-33, 1-35, 1-40, 1-45, 1-50, 1-52, 1-55, 1-60, or 1-63 of SEQ ID NO: 23; and / or the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 31; and / or the portion of CD9 comprises or is a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 32 or 33.

11. The polypeptide of any of claims 1 to 4, wherein the tetraspanin-family protein is CD82 and: the polypeptide does not comprise residues 1-32, 1-35, 1-40, 1-45, 1-46, 1-50, or 1-53 of SEQ ID NO: 24; and / or the polypeptide does not comprise a sequence with at least 25%, 30%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% identity SEQ ID NO: 34; and / or the portion of CD9 comprises or is a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 35 or 36.

12. The polypeptide of any preceding claim, wherein the targeting moiety is capable of specifically binding to a target.

13. The polypeptide of any preceding claim, wherein the targeting moiety is capable of specifically binding to a cell-surface marker of a target cell.

14. The polypeptide of any preceding claim, wherein the targeting moiety is a binding protein, an antibody or antigen-binding fragment thereof, a single-chain variable fragment (scFv), or a single-domain antibody (sdAb).

15. The polypeptide of any preceding claim, wherein the targeting moiety is capable of specifically binding to Plasminogen activator urokinase receptor (PLAUR), Fibroblast growth factor receptor 1 (FGFR1), or Galanin receptor (GALR1).

16. The polypeptide of any preceding claim, wherein the targeting moiety is or comprises SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions.

17. The polypeptide of any preceding claim, wherein the targeting moiety is also a purification moiety and / or wherein the polypeptide further comprises a purification moiety.

18. The polypeptide of claim 17, wherein the purification moiety: comprises an epitope for an antibody, and / or does not comprise an epitope that is also found on other proteins associated with EVs or exosomes, and / or does not comprise an epitope that is found on other proteins associated with human EVs or human exosomes, and / or does not comprise an epitope that is found on other proteins associated with cells for producing EVs or exosomes.

19. The polypeptide of claim 17 or claim 18, wherein the purification moiety is or comprises a FLAG tag, HA- tag, a polyhistidine-tag, or a Myc-Tag.

20. The polypeptide of any preceding claim, wherein the order of components, from N to C, is the targeting moiety, optionally the purification moiety, and the portion of a tetraspanin-family protein.

21. The polypeptide of any preceding claim, further comprising a cargo-binding moiety.

22. The polypeptide of claim 21, wherein the cargo-binding moiety is located to the C-terminal side of the portion of a tetraspanin-family protein.

23. The polypeptide of claim 21 or claim 22, wherein the cargo-binding moiety is a protein domain or a polypeptide.

24. The polypeptide of any one of claims 21 to 23, wherein the cargo-binding moiety is capable of binding to nucleic acid molecules.

25. The polypeptide of any one of claims 21 to 24, wherein the cargo-binding moiety is capable of binding to the C / Dboxstructure in RNA.

26. The polypeptide of any one of claims 21 to 25, wherein the cargo-binding moiety is or comprises a nucleic acid binding domain from or derived from a PUF or Cas endonuclease.

27. The polypeptide of any one of claims 21 to 25, wherein the cargo-binding moiety is or comprises L7Ae or a derivative thereof.

28. The polypeptide of claim 27, wherein the cargo-binding moiety comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 8 and can bind to the C / Dboxstructure.

29. A nucleic acid molecule encoding a polypeptide according to any one of claims 1 to 28.

30. An extracellular vesicle (EV) comprising a polypeptide according to any one of claims 1 to 28.

31. The EV of claim 30, wherein the extracellular vesicle is an exosome.

32. The EV of claim 30 or claim 31, wherein the extracellular vesicle or exosome is obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell.

33. The EV of any one of claims 30 to 32, wherein the N-terminal end of the portion of a tetraspanin-family protein is external to the EV and the C-terminal end of the portion of a tetraspanin-family protein is internal to the EV.

34. The EV of any one of claims 30 to 33, wherein the EV comprises a therapeutic agent.

35. The EV of any one of claims 30 to 34, wherein the polypeptide of any one of claims 21 to 28 is bound to a cargo, optionally wherein the cargo is a therapeutic agent, via the cargo-binding domain.

36. A method of making an EV according to any one of claims 30 to 35, the method comprising: i) transferring a vector encoding a polypeptide of any one of claims 1 to 28 to a cell suitable for producing EVs, and ii) obtaining EVs from said cell.

37. A method of purifying an EV, the method comprising: i) obtaining a population comprising EVs according to any one of claims 30 to 35, ii) contacting the population comprising EVs with a binding agent that can specifically bind to the polypeptide of any one of claims 1 to 28; and iii) isolating EVs bound to said binding agent.

38. A polypeptide that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent and at least a portion of an EV-associated protein.

39. A nucleic acid molecule encoding a polypeptide according to claim 38.

40. A nanoparticle or an EV that comprises a PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent.

41. The nanoparticle or EV of claim 40, wherein the GALR1 binding agent is or comprises SEQ ID NO: 5 or SEQ ID NO: 6 with no more than 10, 8, 6, 5, 4, 3, 2, 1, or no substitutions, insertions, or deletions.

42. The nanoparticle or EV of any claim 40 or claim 41, wherein the nanoparticle or EV comprises a polypeptide according to any one of claims 1 to 28 or is an EV according to any one of claims 30 to 35.

43. The nanoparticle or EV of any one of claims 40 to 42, wherein i) the nanoparticle or EV is an extracellular vesicle is obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell; or ii) the nanoparticle or EV is an exosome obtained or obtainable from a eukaryotic cell, mammalian cell, or human cell; or iii) the nanoparticle or EV is a lipid nanoparticle.

44. The nanoparticle or EV of any one of claims 40 to 43, wherein the nanoparticle or EV comprises a therapeutic agent.

45. The nanoparticle or EV of claim 44, wherein the therapeutic agent is a nucleic acid encoding neurofibromin or a portion or variant thereof.

46. The nanoparticle or EV of claim 44 or claim 45, wherein the therapeutic agent is or comprises a nucleic acid molecule: encoding SEQ ID NO: 13 or a portion or variant thereof; and / or encoding a polypeptide at least 80%, 85%, 90%, 95%, 99%, or 100% similar or identical to SEQ ID NO: 14 or 16; and / or comprising a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% or identical to SEQ ID NO: 19 or 20.

47. A method of making an EV according to any one of claims 40 to 46, the method comprising: i) transferring a vector encoding a PLAUR binding agent, a FGFR1 binding agent, or a GALR1 binding agent to a cell suitable for producing EVs; and ii) obtaining EVs from said cell.

48. A method of purifying an EV, the method comprising: i) obtaining a population comprising EVs according to any one of claims 40 to 46, ii) contacting the population comprising EVs with a purification binding agent that can specifically bind to the PLAUR binding agent, FGFR1 binding agent, or GALR1 binding agent or can specifically bind to a purification moiety; and iii) isolating EVs bound to said purification binding agent.

49. A pharmaceutical composition comprising a polypeptide of any one of claims 1-28 or 38 or a nanoparticle or an EV of any one of claims 30-35 or 40-46.

50. The nanoparticle or EV of any one of claims 34, 35, or 44-46 for use as a medicament.

51. The nanoparticle or EV of any one of claims 34, 35, or 44-46 for use in a method of treating: a pathology associated with Schwann cells, a Schwann cell tumour,a Schwannosis, a Schwannoma, or Charcot-Marie-Tooth disease.

52. The nanoparticle or EV of any one of claims 34, 35, or 44-46 for use in a method of treating Neurofibromatosis type 1 (NF1).

53. An EV for use in a method of treating NF1, wherein the EV displays a galanin peptide or variant thereof on the outside of the EV, and the EV comprises a nucleic acid that encodes neurofibromin or a portion or variant thereof, wherein the neurofibromin, portion, or variant has GTPase-activating activity.

54. An exosome, optionally a human exosome, for use in a method of treating NF1, wherein the exosome displays a galanin peptide or variant thereof on the outside of the exosome, and the exosome comprises a nucleic acid that encodes neurofibromin or a portion or variant thereof, wherein the neurofibromin, portion, or variant has GTPase-activating activity.

55. An LNP for use in a method of treating NF1, wherein the LNP displays a galanin peptide or variant thereof on the outside of the LNP, and the LNP comprises a nucleic acid that encodes neurofibromin or a portion or variant thereof, wherein the neurofibromin, portion, or variant has GTPase-activating activity.

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