Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system

• 成果类型: Article
• 署名作者: Hao, Liangliang; Boehnke, Natalie; Elledge, Susanna K.; Harzallah, Nour-Saida; Zhao, Renee T.; Cai, Eva; Feng, Yu-Xiong; Neaher, Sofia; Fleming, Heather E.; Gupta, Piyush B.; Hammond, Paula T.; Bhatia, Sangeeta N.
• 署名单位: Massachusetts Institute of Technology (MIT); University of Minnesota System; University of Minnesota Twin Cities; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11889
• DOI: 10.1073/pnas.2307802121
• 发表日期: 2024-03-12
• 关键词: baf57; nanoparticles; sirna; DRUG

摘要

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 - bylayer 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.