Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system
Name
hao-et-al-targeting-and-monitoring-ovarian-cancer-invasion-with-an-rnai-and-peptide-delivery-system.pdf
Description
Published version
Size
5.26 MB
Format
Adobe PDF
Checksum (MD5)
96bcd235b87688a0acc3b15a4803032c
Author(s)
Hao, Liangliang
Boehnke, Natalie
Elledge, Susanna K
Harzallah, Nour-Saïda
Zhao, Renee T
Cai, Eva
Feng, Yu-Xiong
Neaher, Sofia
Fleming, Heather E
Gupta, Piyush B
Date Issued
March 4, 2024
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Citation
L. Hao,N. Boehnke,S.K. Elledge,N. Harzallah,R.T. Zhao,E. Cai,Y. Feng,S. Neaher,H.E. Fleming,P.B. Gupta,P.T. Hammond, & S.N. Bhatia, Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system, Proc. Natl. Acad. Sci. U.S.A. 121 (11) e2307802121.
Version
Final published version
Abstract
RNA interference (RNAi) therapeutics are an emerging class of medicines that selectively target mRNA transcripts to silence protein production and combat disease. Despite the recent progress, a generalizable approach for monitoring the efficacy of RNAi therapeutics without invasive biopsy remains a challenge. Here, we describe the development of a self-reporting, theranostic nanoparticle that delivers siRNA to silence a protein that drives cancer progression while also monitoring the functional activity of its downstream targets. Our therapeutic target is the transcription factor SMARCE1, which was previously identified as a key driver of invasion in early-stage breast cancer. Using a doxycycline-inducible shRNA knockdown in OVCAR8 ovarian cancer cells both in vitro and in vivo, we demonstrate that SMARCE1 is a master regulator of genes encoding proinvasive proteases in a model of human ovarian cancer. We additionally map the peptide cleavage profiles of SMARCE1-regulated proteases so as to design a readout for downstream enzymatic activity. To demonstrate the therapeutic and diagnostic potential of our approach, we engineered self-assembled layer-by-layer nanoparticles that can encapsulate nucleic acid cargo and be decorated with peptide substrates that release a urinary reporter upon exposure to SMARCE1-related proteases. In an orthotopic ovarian cancer xenograft model, theranostic nanoparticles were able to knockdown SMARCE1 which was in turn reported through a reduction in protease-activated urinary reporters. These LBL nanoparticles both silence gene products by delivering siRNA and noninvasively report on downstream target activity by delivering synthetic biomarkers to sites of disease, enabling dose-finding studies as well as longitudinal assessments of efficacy.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Harvard-MIT Program in Health Sciences and Technology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies
Massachusetts Institute of Technology. Department of Chemical Engineering
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.1073/pnas.2307802121
