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Genetic engineering represents a robust strategy for loading proteins of interest into EVs. Identification of EV\u2010enriched proteins facilitates protein cargo loading efficiency. Many EV\u2010enriched proteins are sorted into EVs via an endosomal sorting complex required for transport (ESCRT)\u2010dependent pathway. In parallel, viruses hijack this EV biosynthesis machinery via conserved late domain motifs to promote egress from host cells. Inspired by the similarity of biogenesis between EVs and viruses, we developed a synthetic, Late domain\u2010based EV scaffold protein that enables the display of a set of single chain variable fragments (scFvs) on the EV surface. We named this scaffold the Late domain\u2010based exosomal antibody surface display platform (LEAP). We applied the LEAP scaffold to reprogramme HEK293T cell\u2010derived EVs to elicit T\u2010cell anti\u2010tumor immunity by simultaneously displaying \u03b1PD\u2010L1 and \u03b1CD3 scFvs on the EV surface (denoted as \u03b1PD\u2010L1\u00d7\u03b1CD3 bispecific T\u2010cell engaging exosomes, BiTExos). We demonstrated that \u03b1PD\u2010L1\u00d7\u03b1CD3 BiTExos actively redirected T cells to bind to PD\u2010L1<jats:sup>+<\/jats:sup> tumor cells, promoting T\u2010cell activation, proliferation and tumoricidal cytokine production. Furthermore, the \u03b1PD\u2010L1\u00d7\u03b1CD3 BiTExos promoted T\u2010cell infiltration into the tumor microenvironment to mitigate the tumor burden in vivo. Our study suggested that the LEAP scaffold may serve as a platform for EV surface display and could be applied for a broad range of EV\u2010based biomedical applications.<\/jats:p>","DOI":"10.1002\/jev2.12490","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T08:40:25Z","timestamp":1721896825000},"source":"Crossref","is-referenced-by-count":28,"title":["Extracellular vesicle surface display of \u03b1PD\u2010L1 and \u03b1CD3 antibodies via engineered late domain\u2010based scaffold to activate T\u2010cell anti\u2010tumor immunity"],"prefix":"10.1002","volume":"13","author":[{"given":"Rui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Sun Yat\u2010sen Memorial Hospital, Sun Yat\u2010sen University  Guangzhou Guangdong P.R. 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China"},{"name":"Medical Research Center Sun Yat\u2010sen Memorial Hospital, Sun Yat\u2010sen University  Guangzhou Guangdong P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Sun Yat\u2010sen Memorial Hospital, Sun Yat\u2010sen University  Guangzhou Guangdong P.R. China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou Guangdong P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuepeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Sun Yat\u2010sen Memorial Hospital, Sun Yat\u2010sen University  Guangzhou Guangdong P.R. 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