HER3-targeted protein chimera forms endosomolytic capsomeres and self-assembles into stealth nucleocapsids for systemic tumor homing of RNA interference in vivo
Year: 2019
Type: article
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.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkz900
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Funders: U.S. Department of Defense, Avon Foundation for Women, Cedars-Sinai Medical Center, National Institutes of Health, California State University, Northridge, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences
Awards: G1335075256, BUILD PODER II, G2800195642, G2854196284, UCLA Clinical and Translational Science Institute, G3841518252, G395839407, G4119534169, G4130299715, G4384252071, G5850682332, TARGETING SIRNA MISSILES TO HER2+ BREAST CANCER, Multidisciplinary Pulmonary Research Training Program, NANOBIOLOGIC TARGETING OF METASTATIC BREAST TUMORS, G7655509568, BUILD PODER II, Protein-DNA Drug Carriers for Targeting Drug-Resistant Tumors, G8454392890, G9000128048, G9000350627, G962329248
OpenAlex ID: W2980424604