Surface‐Engineered Extracellular Vesicles with CDH17 Nanobodies to Efficiently Deliver Imaging Probes and Chemo‐Photothermal Drugs for Gastric Cancer Theragnostic

Abstract Extracellular vesicles (EVs) are widely used as natural nanoparticles to deliver various cargos for disease diagnosis and therapy. However, unmodified EVs cannot efficiently transport the cargos to desired sites due to non‐specific uptake. Here, a delivery system is designed to display nanobodies against cadherin 17 (CDH17) on the surface of EVs isolated from HEK‐293 cells and loaded with dye Indocyanine green (ICG) and/or anti‐cancer drug dinitroazetidine derivative RRx‐001, a blocker for CD47/ signal regulatory protein alpha (SIRPα) axis. CDH17 is a promising target for gastric cancer (GC) therapy. In this study, ICG loaded in the EVs engineered with CDH17 nanobodies can realize rapid tumor imaging in a CDH17‐positive GC model and can produce significant anti‐tumor photothermal therapeutic (PTT) effect after irradiation. Meanwhile, PTT effect can induce immunogenic cell death and macrophage polarization from M2 to M1 phenotype. The engineered EVs loaded with RRx‐001 can significantly repress GC tumor growth. Finally, dual loading of ICG/RRx‐001 in engineered EVs show maximal anti‐tumor efficacy in both cancer cell and patient‐derived GC models after only single injection. Collectively, CDH17 nanobody‐functionalized EVs loaded with ICG and/or RRx‐001 hold great promise to image and treat GC by combining fluorescent dye‐induced PTT with chemotherapy.