Efficient intracellular delivery of p53 protein by engineered protein crystals restores tumor suppressing function in vivo.

Zaofeng Yang, Marianne M M Lee, Michael K Chan

Biomaterials 2021 Apr

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Direct delivery of proteins into cells holds significant potential for basic research and drug development. However, the poor endosomal escape of conventional delivery strategies remains a challenge, thus limiting the clinical translation of many protein therapeutics. Herein, we report that engineered Cry3Aa protein (Pos3Aa) crystals formed naturally within Bacillus thuringiensis can serve as a vehicle for efficient cytosolic delivery of bioactive proteins. We showed that Pos3Aa-mediated delivery of tumor suppressor p53 protein, a promising therapeutic candidate found to be inactivated in nearly half of human cancers, resulted in the restoration of p53 function in p53-deficient cancer cells, and thereby sensitized them to 5-fluorouracil chemotherapy as demonstrated in in vitro and in vivo models. Our results validate that Pos3Aa crystals can be a robust and effective platform for the cytosolic delivery of effector proteins, and suggest that efficient uptake and endosomal escape could be critical for efficacious p53 protein-based cancer therapy. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Zaofeng Yang, Marianne M M Lee, Michael K Chan. Efficient intracellular delivery of p53 protein by engineered protein crystals restores tumor suppressing function in vivo. Biomaterials. 2021 Apr;271:120759