Early Detection and Inhibition of Post‐Surgical Cancer Recurrence by Synthetic Extracellular Vesicles

ABSTRACT Early detection of post‐surgical cancer recurrence could improve patient survival. Endogenous biomarkers remain at the forefront of early detection efforts, but many lack the requisite sensitivity and specificity to effectively guide clinical management. Herein, we employed a synthetic biomarker approach by embedding a tumor specific promoter‐driven synthetic extracellular vesicles (EVs)‐generating system at the tumor resection site. This system reprograms tumor cells to secrete synthetic EVs expressing engineered miR‐26a (E‐miR‐26a, a synthetic barcoding sequence) or PD‐1 (a PD‐L1‐blocking agent), thereby achieving early detection and inhibition of post‐surgical tumor recurrence. In a mouse model of post‐resection tumor recurrence, we demonstrated that monitoring of E‐miR‐26a‐expressing EVs in blood facilitated more timely detection of recurrence than bioluminescence imaging. We further validated that the strategy could detect tumors at early stage across mice with varying tumor burdens. Furthermore, PD‐1‐expressing EVs could bind to PD‐L1 on tumor cells, thereby enhancing T cells activation and antitumor efficacy. Collectively, our findings provide an integrated strategy for the early detection and treatment of post‐surgical tumor recurrence, with the potential to improve long‐term outcomes for cancer patients.