Chemically Programmable DNA Nanostructures for Multiplexed High-Throughput Screening of Cardiovascular Therapeutics

Chemically Programmable DNA Nanostructures for Multiplexed High-Throughput Screening of Cardiovascular Therapeutics | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Chemically Programmable DNA Nanostructures for Multiplexed High-Throughput Screening of Cardiovascular Therapeutics Ke-Jia Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5941741/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The development of small-molecule therapeutics for cardiac hypertrophy is limited by the lack of high-throughput screening platforms capable of multiplexed molecular detection. Here, we present the Multifunctional Nucleic-acid-label-free hESC-CMs Molecular Evolution ( MNCME ) platform, which integrates tetrahedral DNA nanostructures with human embryonic stem cell-derived cardiomyocytes (hESC-CMs) for chemically programmable, label-free detection of DNA, RNA, proteins, and small molecules. By dynamically substituting three label-free primers, MNCME enables flexible molecular profiling and rapid target adaptation. Machine learning-assisted analysis of known anti-hypertrophic compounds identified key molecular signatures, optimizing high-throughput screening workflows. Structurally organized into five functional zones, MNCME screened a 600-compound library, identifying nine bioactive molecules, including caffeic acid (CA), previously unrecognized for its cardioprotective potential. Mechanistic studies revealed that CA modulates ATP synthesis, Ca²⁺ homeostasis, and Mucin-1 signaling, with validation in cellular and in vivo models. By integrating DNA nanotechnology, chemical biology, and high-throughput phenotypic screening, MNCME provides a scalable and versatile platform for accelerating the discovery of small-molecule modulators targeting cardiac hypertrophy. This approach has the potential to transform therapeutic development for cardiovascular diseases and other complex pathologies, offering a powerful tool for both fundamental research and clinical translation. Chemical Biology DNA framework High-throughput screening Human embryonic stem cell-derived cardiomyocytes Cardiac hypertrophy Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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