In this study, extracellular vesicles (EVs) are reimagined as more than just a cellular waste disposal system and are repurposed for cancer immunotherapy. Potent oncolytic EVs (bRSVF-EVs) loaded with misfolded proteins (MPs) are engineered, which are typically considered cellular debris. By impairing lysosomal function using bafilomycin A1 and expressing the respiratory syncytial virus F protein, a viral fusogen, MPs are successfully loaded into the EVs expressing RSVF. bRSVF-EVs preferentially transplant a xenogeneic antigen onto cancer cell membranes in a nucleolin-dependent manner, triggering an innate immune response. Furthermore, bRSVF-EV-mediated direct delivery of MPs into the cancer cell cytoplasm initiates endoplasmic reticulum stress and immunogenic cell death (ICD). This mechanism of action leads to substantial antitumor immune responses in murine tumor models. Importantly, when combined with PD-1 blockade, bRSVF-EV treatment elicits robust antitumor immunity, resulting in prolonged survival and complete remission in some cases. Overall, the findings demonstrate that utilizing tumor-targeting oncolytic EVs for direct cytoplasmic delivery of MPs to induce ICD in cancer cells represents a promising approach for enhancing durable antitumor immunity.
Bibliographical noteFunding Information:
The authors would like to acknowledge all the staff for assistance with all experiments. This work was supported by SHIFTBIO.INC, a Korea University Grant (K2225811), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2017R1A3B1023418), the National Cancer Center of Korea, the KU‐KIST Graduate School of Converging Science and Technology Program, and the KIST Institutional Program.
© 2023 The Authors. Small published by Wiley-VCH GmbH.
- cancer immunotherapy
- endoplasmic reticulum (ER) stress
- extracellular vesicles
- immunogenic cell death
- misfolded proteins
- respiratory syncytial virus F proteins
ASJC Scopus subject areas
- General Chemistry
- General Materials Science
- Engineering (miscellaneous)