Biomimetic Nanovaccines Restore Immunosuppressive Tumor Antigen-Presenting Cells via the Saposin-Feeding Strategy

Abstract

Cancer cell membrane-derived biomimetic nanovaccines have shown tremendous potential in cancer immunotherapy. However, their efficacy is restricted by the insufficient cross-presentation of cell membrane-associated antigens. Saposins (SAs), which are vital for membrane vesicle disintegration and cell membrane-associated antigen presentation, are severely deficient in the antigen-presenting cells (APCs) within tumors. Herein, we propose a complementary strategy for increasing the efficacy of biomimetic nanovaccines via the use of SAs. Biomimetic nanovaccines were designed using cancer cell membrane shells to provide a comprehensive array of tumor-associated antigens and reactive oxygen species (ROS)-responsive nanoparticle cores that allowed the codelivery of cytosine–guanine dinucleotides (CpGs) and SAs. The biomimetic nanovaccines were ROS-responsive and highly internalized by APCs, which enabled the release of CpGs and SAs in the endo/lysosomes of APCs. Furthermore, biomimetic nanovaccines increased the activation of immunosuppressive APCs and enhanced T-cell priming by delivering SAs to the APCs. Consequently, biomimetic nanovaccines loaded with SAs not only suppressed tumor growth but also exhibited excellent therapeutic effects in combination with immune checkpoint blockade strategies. Overall, our study provides insights into the development of enhanced biomimetic nanovaccines via integrating SAs and offers a promising strategy for highly effective cancer immunotherapy.