An Engineered Extracellular Vesicle With Enhanced Tumor and Lymph Nodes Targeting as siRNA Delivery System for Robust...

Area of Science:

• Oncology
• Immunology
• Nanotechnology

Background:

• Tumor-derived extracellular vesicles (EVs) show potential as personalized cancer vaccines but lack specific tissue targeting.
• Engineering EVs can enhance their immunotherapeutic capabilities.

Purpose of the Study:

• To engineer tumor-derived EVs for improved targeting and therapeutic efficacy in cancer immunotherapy.
• To develop a novel cancer vaccine platform combining targeted EVs with immune checkpoint blockade.

Main Methods:

• Engineered tumor EVs with DP7-C peptide (DP-EVs) for enhanced targeting to lymph nodes and tumors.
• Loaded DP-EVs with small interfering RNA targeting PD-L1 (siPD-L1) to create DP-EVs/siPD-L1.
• Evaluated in vivo efficacy in tumor-bearing mice, assessing tumor growth, survival, immune activation, and tumor microenvironment modulation.

Main Results:

• DP-EVs demonstrated enhanced accumulation in lymph nodes and tumors with improved cellular uptake and endosomal escape.
• DP-EVs/siPD-L1 effectively suppressed PD-L1 expression in dendritic cells and tumor cells.
• DP-EVs/siPD-L1 significantly inhibited tumor growth and prolonged survival in mice.
• Therapeutic effects were linked to immune activation and remodeling of the immunosuppressive tumor microenvironment.

Conclusions:

• Engineered EVs (DP-EVs/siPD-L1) represent a promising cancer vaccine platform.
• This strategy synergistically activates antitumor immunity and reverses tumor microenvironment-mediated immunosuppression.
• The engineered EV platform offers a translatable approach for advanced cancer immunotherapy.