Harnessing Oncolytic Extracellular Vesicles for Tumor Cell-Preferential Cytoplasmic Delivery of Misfolded Proteins for Cancer Immunotherapy

Gi Beom Kim, Seonghyun Kim, Yeong Ha Hwang, Seohyun Kim, Inkyu Lee, Seong A. Kim, Jiyoung Goo, Yoosoo Yang, Cherlhyun Jeong, Gi Hoon Nam, In San Kim

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number2300527
JournalSmall
Volume19
Issue number37
DOIs
Publication statusPublished - 2023 Sept 13

Bibliographical note

Funding 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.

Publisher Copyright:
© 2023 The Authors. Small published by Wiley-VCH GmbH.

Keywords

  • cancer immunotherapy
  • endoplasmic reticulum (ER) stress
  • extracellular vesicles
  • immunogenic cell death
  • misfolded proteins
  • respiratory syncytial virus F proteins
  • xenogenization

ASJC Scopus subject areas

  • Biotechnology
  • General Chemistry
  • Biomaterials
  • General Materials Science
  • Engineering (miscellaneous)

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