Abstract

Tumor‐derived extracellular vesicles (EVs) are a class of natural nanocarriers with phospholipid bilayers that show great promise as personalized cancer vaccine platforms due to their ability to carry tumor‐specific antigens. However, their immunotherapeutic potential is hindered by limited tissue‐specific targeting. In this study, we engineered tumor cell‐derived EVs using an immunomodulatory peptide, DP7‐C, to generate DP7‐C engineered EVs (DP‐EVs). These DP‐EVs exhibited significantly enhanced accumulation in both lymph nodes and tumor tissues. Additionally, they demonstrated improved cellular uptake and facilitated more efficient endosomal escape. To further enhance the therapeutic efficacy, programmed cell death 1 ligand 1 targeting small interfering RNA (siPD‐L1) was loaded into the DP‐EVs, resulting in DP‐EVs/siPD‐L1. This formulation enabled concurrent suppression of PD‐L1 expression in both dendritic cells (DCs) and tumor cells. In vivo experiments showed that DP‐EVs/siPD‐L1 significantly inhibited tumor growth and prolonged survival in tumor‐bearing mice. The observed antitumor effect was attributed to the immune activation in the lymph nodes and the remodeling of the immunosuppressive tumor microenvironment (TME). Collectively, our findings demonstrate that DP‐EVs/siPD‐L1 functions as an effective therapeutic vaccine, which synergistically activates antitumor immunity and reverses immunosuppression through targeted PD‐L1 blockade. This engineered EV platform represents a promising and translatable strategy for cancer immunotherapy. Simple incubation with DP7‐C enables the generation of extracellular vesicles (DP‐EVs) with enhanced both tumor and lymph nodes targeting properties. DP‐EVs/siPD‐L1 can effectively inhibit tumor growth and greatly prolong the survival of tumor bearing mice through immune response activation and tumor microenvironment reprogramming.