Extracellular vesicles (EVs) are natural delivery vectors and mediators of biological signals. This study demonstrates that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G (IgG) antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, the study shows targeting of EVs to cancer cells expressing the human epidermal receptor 2 (HER2) or programmed-death ligand 1 (PD-L1), as well as reduced tumor burden and extended survival in mice with subcutaneous melanoma when systemically injected with EVs displaying an antibody for PD-L1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies, and antibody-drug conjugates. The study presents a highly modular technology for EV therapeutics. Using molecular engineering tools, the researchers developed EVs that can bind the Fc portion of antibodies, allowing the variable regions to be displayed for antigen recognition. The Fc-binding EVs (Fc-EVs) can be decorated with different types of antibody and thus be targeted to essentially any tissues of interest. The Fc-EVs technology is designed as a targeted cancer therapy using tumor-specific therapeutic antibodies to guide the EVs to tumor cells and deliver antitumor drugs. The study optimized Fc-EVs by screening EV-sorting proteins and Fc-binding domains. The results showed that the Fc-EVs could be efficiently targeted to cancer cells expressing HER2 or PD-L1. The Fc-EVs were characterized and confirmed to bind antibodies specifically. The study also demonstrated that Fc-EVs could be used for targeted delivery in vivo, with increased accumulation in tumor tissue when guided by PD-L1-Ab. When loaded with the chemotherapeutic drug doxorubicin, the Fc-EVs showed improved anti-tumor effects. The study also showed that Fc-EVs could be used for targeted delivery in vivo, with increased accumulation in tumor tissue when guided by PD-L1-Ab. When loaded with the chemotherapeutic drug doxorubicin, the Fc-EVs showed improved anti-tumor effects. The study concluded that the Fc-EV technology offers a combined EV-antibody therapy in which targeting and/or therapeutic antibodies facilitate targeted EV delivery with therapeutic cargo that can generate a synergistic effect. The technology could be applied to a myriad of indications and used in multiple combinations, not only limited to classical antibody but could also include Fc-fused proteins, antibody-drug conjugates, and bi-specific antibodies.Extracellular vesicles (EVs) are natural delivery vectors and mediators of biological signals. This study demonstrates that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G (IgG) antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, the study shows targeting of EVs to cancer cells expressing the human epidermal receptor 2 (HER2) or programmed-death ligand 1 (PD-L1), as well as reduced tumor burden and extended survival in mice with subcutaneous melanoma when systemically injected with EVs displaying an antibody for PD-L1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies, and antibody-drug conjugates. The study presents a highly modular technology for EV therapeutics. Using molecular engineering tools, the researchers developed EVs that can bind the Fc portion of antibodies, allowing the variable regions to be displayed for antigen recognition. The Fc-binding EVs (Fc-EVs) can be decorated with different types of antibody and thus be targeted to essentially any tissues of interest. The Fc-EVs technology is designed as a targeted cancer therapy using tumor-specific therapeutic antibodies to guide the EVs to tumor cells and deliver antitumor drugs. The study optimized Fc-EVs by screening EV-sorting proteins and Fc-binding domains. The results showed that the Fc-EVs could be efficiently targeted to cancer cells expressing HER2 or PD-L1. The Fc-EVs were characterized and confirmed to bind antibodies specifically. The study also demonstrated that Fc-EVs could be used for targeted delivery in vivo, with increased accumulation in tumor tissue when guided by PD-L1-Ab. When loaded with the chemotherapeutic drug doxorubicin, the Fc-EVs showed improved anti-tumor effects. The study also showed that Fc-EVs could be used for targeted delivery in vivo, with increased accumulation in tumor tissue when guided by PD-L1-Ab. When loaded with the chemotherapeutic drug doxorubicin, the Fc-EVs showed improved anti-tumor effects. The study concluded that the Fc-EV technology offers a combined EV-antibody therapy in which targeting and/or therapeutic antibodies facilitate targeted EV delivery with therapeutic cargo that can generate a synergistic effect. The technology could be applied to a myriad of indications and used in multiple combinations, not only limited to classical antibody but could also include Fc-fused proteins, antibody-drug conjugates, and bi-specific antibodies.