Targeted co-delivery of curcumin and TRAIL via engineered extracellular vesicles: a synergistic therapy against...

Renal cell carcinoma (RCC) is a resistant malignancy with a rising global incidence, thereby highlighting an urgent need for innovative treatment strategies. Curcumin (CUR), a natural polyphenolic compound, is promising for cancer treatment. However, its clinical translation has been hindered by poor bioavailability, low solubility, and rapid elimination. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-expressing extracellular vesicle (EV-T) has been proven to be an ideal platform for integrating TRAIL-sensitizing agents with TRAIL for synergistic cancer therapies. Yet, no studies have explored whether CUR could be encapsulated in EV-Ts to achieve synergistic anticancer effects. Herein we hypothesize that EV-T modified by the arginine-glycine-aspartic acid (RGD) tripeptide (denoted RGD@EV-T) exhibits enhanced tumor tropism. By loading CUR into RGD@EV-T, we could construct a novel nano-CUR formulation, namely RGD@EV-T-CUR, for co-delivery of CUR and TRAIL to achieve synergistic therapy for RCC. The RGD@EV-T was first prepared via anchoring CP05-RGD mediated integration, then CUR was efficiently encapsulated with an encapsulation rate of 53.4% to make RGD@EV-T-CUR. The RGD modification significantly enhanced the tumor tropism of EV-T by approximately 4-fold. Importantly, RGD@EV-T-CUR achieved synergistically enhanced apoptosis-inducing rate (74.9 ± 5.3%) in TRAIL-resistant RCC cells. Notably, RGD@EV-T-CUR demonstrated synergistically improved tumor growth inhibition efficacy (93.3%) compared to either CUR (28.7%) or RGD@EV-T (41.7%) monotherapy in a subcutaneous RCC xenograft tumor model in mice. The synergistic therapeutic efficacy is associated with the concurrent upregulation of death receptor 5 (DR5), downregulation of anti-apoptotic proteins, and suppression of the nuclear factor-kappaB signaling pathway. Collectively, RGD@EV-T-CUR potentially constitutes a novel cancer therapy, which is highly effective and safe for RCC treatment.