{"doi":"10.1002/jev2.12032","title":"Hitting the Bullseye: Are extracellular vesicles on target?","abstract":"Great strides have been made in advancing extracellular vesicles (EVs) to clinical testing (Hu, Wolfram, & Srivastava, 2020; Lener et al., 2015, Reiner et al., 2017; Rohde, Pachler, & Gimona, 2019). By late 2020, approximately 250 trials that utilize EVs in some way had been registered in clinicaltrials.gov. Diagnostic, prognostic, and monitoring uses of EVs are evident in these registrations as well as applications of EVs in therapeutics. Interest in EVs stems in part from their biology (Yáñez-Mó et al., 2015). They are involved in natural processes of communication in the body and have a perceived safety profile that features low immunogenicity. Additionally, EVs are ‘targetable’. Display of specific proteins, and possibly other biomolecules, allows EVs to be sorted to certain cell types and tissues or away from undesired recipients (Ferrantelli, Chiozzini, Leone, Manfredi, & Federico, 2020; Pirisinu et al., 2020; Walker et al., 2019). EV engineering, by manipulating the EV source or by altering EVs post-production, can be used to enhance such targeting. Modified EVs have been used for some time as delivery vehicles for small molecule drugs and natural products, short hairpin RNA (shRNA), short interfering (siRNA), plasmid DNA and microRNAs (Sun et al., 2010; Tian et al., 2014) (Figure 1). However, a key factor in the success of this and other EV therapies is whether and how EVs can be targeted to, or away from, specific cells. In this editorial, we offer our perspectives on EV targeting as organizers and participants in an ISEV Workshop on the topic, which has been followed by extensive subsequent discussions. We first review several features of EVs that make them suitable and desirable as therapeutic platforms. We then provide several examples of strategies to target EVs to specific cell types and to avoid recognition by other cells. Along the way, the concept and implications of ‘targeting’ are examined critically. In some applications, success of an EV therapy, like real estate, may be all about ‘location, location, location’: physically applying the EVs in the right place. And of course, many aspects of EV production influence eventual use and efficacy. Finally, we examine how targeting (or selective retention) of EVs can be confirmed in vivo. EVs are nano-sized membranous structures released by cells into the extracellular space, including most, if not all, body fluids (Minciacchi, Freeman, & Di Vizio, 2015; Witwer & Théry, 2019). Their multiple biological functions range from removal of harmful materials from the cell to trophic support and to mediation of intercellular and interorgan communication. EVs can serve as messengers by binding to signalling receptors on recipient cells or via transfer of functional cargo such as microRNAs (miRNAs), mRNAs, proteins and lipids. EVs can infiltrate biological barriers through transcytotic processes or, for the smaller EVs, through small vessel fenestrations, e.g. in the tumour microenvironment. Furthermore, EVs generally show minimal native immunogenicity when compared with artificial nanoparticles, and the immune response can be avoided using autologous EVs (Villa, Quarto, & Tasso, 2019). EVs can be modified by loading specific cargo or by changing EV surface molecules to target the EV to, or away from, specific cell types (Patel, Santoro, Born, Fisher, & Jay, 2018) (Figure 1). The use of EVs is currently being evaluated as a therapeutic strategy for treatment of variety of diseases including cancers (Pirisinu et al., 2020; Walker et al., 2019), cardiovascular diseases (De Abreu et al., 2020), neurogenerative diseases (Ferrantelli et al., 2020) and diabetes (Noren Hooten & Evans, 2020; Xiao et al., 2019). Many of these pre-clinical studies have shown promise in in vivo models and use EVs to deliver specific cargo such as miRNAs, siRNAs and proteins. Most recently, several interventional clinical trials have begun to assess the efficacy of EVs as treatment for COVID-19, acute m","journal":"Journal of Extracellular Vesicles","year":2020,"id":119263,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9449,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":398167,"name":"María Yáñez‐Mó","orcid":"0000-0001-7484-2866","position":1,"is_corresponding":false},{"id":554960,"name":"Rachel M. DeRita","orcid":null,"position":2,"is_corresponding":false},{"id":553867,"name":"Ashley E. Russell","orcid":"0000-0002-9365-2985","position":3,"is_corresponding":false},{"id":312191,"name":"Peter J. Quesenberry","orcid":"0000-0002-7370-5787","position":4,"is_corresponding":false},{"id":405566,"name":"Bharat Ramratnam","orcid":null,"position":5,"is_corresponding":false},{"id":233167,"name":"Paul D. Robbins","orcid":"0000-0003-1068-7099","position":6,"is_corresponding":false},{"id":294390,"name":"Dolores Di Vizio","orcid":"0000-0002-9787-6556","position":7,"is_corresponding":false},{"id":553868,"name":"Sicheng Wen","orcid":"0000-0002-4428-3634","position":8,"is_corresponding":false},{"id":215735,"name":"Kenneth W. Witwer","orcid":"0000-0003-1664-4233","position":9,"is_corresponding":false},{"id":291280,"name":"Lucia R. Languino","orcid":"0000-0001-9011-7031","position":10,"is_corresponding":false},{"id":345471,"name":"Nicole Noren Hooten","orcid":"0000-0002-1683-3838","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:14:08.313144Z","pmid":"33708359","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}