AS1411-Bivalent-Cholesterol-Anchor Equipped with Zinc Phthalocya-Nine Enables NK Cells Derived Exosomes to Realize Effective Tumor-Tropism Photodynamic Therapy

Background/Objectives: Benefiting from their outstanding tumor-penetrating ability and cytotoxic proteins and cytokines, natural-killer-cell-derived exosomes (NEX) show great potential for cell-free tumor immunotherapy. To meet the clinical tumor therapeutic need, engineered NEX are highly required to further enhance their tumor-tropism and antitumor abilities. Methods: We proposed a NEX engineering strategy, using a structure of AS1411-bivalent-cholesterol (B-Chol) anchor equipped with photosensitizer zinc phthalocyanine (ZnPc) attached on the membrane of NEX to form A-P-NEX. It not only preferably maintains the spatial structure of the AS1411 aptamer via a B-Chol anchor contributing to the tumor-tropism and stability of NEX but also significantly improves the photodynamic therapy (PDT) effect by firmly binding ZnPc in the unique G-quadruplex structure in the AS1411 aptamer. Results: The results showed that A-P-NEX could promote the precise uptake of NEX and ZnPc by tumor cells and produce obvious synergistic NEX-based immunotherapy and PDT upon laser irradiation, demonstrating excellent targeted antitumor effects both in vitro and in vivo. Conclusions: This study demonstrates a reliable NEX engineering strategy and paves the way for developing a useful tumor-tropism PDT method.