Antibody functionalized curcuma-derived extracellular vesicles loaded with doxorubicin overcome therapy-induced senescence and enhance chemotherapy

Conventional cancer treatments often induce a sustained DNA damage response (DDR) in tumor cells, leading to therapy-induced senescence (TIS), characterized by permanent cell cycle arrest and resistance to apoptosis. These senescent cells secrete senescence-associated secretory phenotypes (SASP), which can promote tumor progression and create an immunosuppressive microenvironment. This study introduces a novel approach to enhance chemotherapy efficacy by using functionalized curcuma-derived extracellular vesicles (DR5-CNV/DOX) to target and eliminate senescent tumor cells and inhibit their SASP. Curcuma-derived extracellular vesicles (CNV) were loaded with the chemotherapeutic drug doxorubicin (DOX) and surface-modified with an antibody targeting death receptor 5 (DR5), which is overexpressed on senescent tumor cells. In vitro experiments demonstrated that DR5-CNV/DOX effectively targeted senescent tumor cells, promoting apoptosis and suppressing SASP production. In vivo studies confirmed the inhibition of epithelial-mesenchymal transition (EMT) initiation, angiogenesis, and modulation of the tumor immune microenvironment, enhancing chemotherapy efficacy and demonstrating promising biocompatibility. This study highlights the potential of plant-derived extracellular vesicles as a novel drug delivery system to overcome senescent tumor cells and their SASP.