HER3-targeted protein chimera forms endosomolytic capsomeres and self-assembles into stealth nucleocapsids for systemic tumor homing of RNA interference in vivo
Abstract
RNA interference represents a potent intervention for cancer treatment but requires a robust delivery agent for transporting gene-modulating molecules, such as small interfering RNAs (siRNAs). Although numerous molecular approaches for siRNA delivery are adequate in vitro, delivery to therapeutic targets in vivo is limited by payload integrity, cell targeting, efficient cell uptake, and membrane penetration. We constructed nonviral biomaterials to transport small nucleic acids to cell targets, including tumor cells, on the basis of the self-assembling and cell-penetrating activities of the adenovirus capsid penton base. Our recombinant penton base chimera contains polypeptide domains designed for noncovalent assembly with anionic molecules and tumor homing. Here, structural modeling, molecular dynamics simulations, and functional assays suggest that it forms pentameric units resembling viral capsomeres that assemble into larger capsid-like structures when combined with siRNA cargo. Pentamerization forms a barrel lined with charged residues mediating pH-responsive dissociation and exposing masked domains, providing insight on the endosomolytic mechanism. The therapeutic impact was examined on tumors expressing high levels of HER3/ErbB3 that are resistant to clinical inhibitors. Our findings suggest that our construct may utilize ligand mimicry to avoid host attack and target the siRNA to HER3+ tumors by forming multivalent capsid-like structures.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 16, 2019
- Source ID
- 10.1093/nar/gkz900
Entities
People
- Altan Rentsendorj
- David Chu
- Dustin Srinivas
- Felix Alonso-Valenteen
- Jae Youn Hwang
- Jay Lubow
- Jessica Sims
- Lali K Medina-Kauwe
- Ravinder Abrol
- Sayuri Pacheco
- Simoun Mikhael
- Tianxin Miao
Organizations
- Avon Foundation for Women
- California State University
- California State University, Northridge
- Cedars-Sinai Medical Center
- Daegu Gyeongbuk Institute of Science and Technology
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of California