Peptide-lipid nanoparticle-mediated delivery of p53-circRNA synergizes with everolimus for dual suppression of PI3K/AKT/mTOR pathway

Peptide-lipid nanoparticle-mediated delivery of p53-circRNA synergizes with everolimus for dual suppression of PI3K/AKT/mTOR pathway | 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 Article Peptide-lipid nanoparticle-mediated delivery of p53-circRNA synergizes with everolimus for dual suppression of PI3K/AKT/mTOR pathway Xing-Jie Liang, Weisi Yuan, Qihan Xie, Meiping Song, Yinan Du, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8092851/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 PI3K/AKT/mTOR (PAM) pathway is aberrantly activated in about 50% of human cancers, serving as a critical therapeutic target. However, the efficacy of PAM inhibitors is often compromised by intrinsic resistance, especially in p53-deficient non-small cell lung cancer (NSCLC). Here, we develop peptide-lipid nanoparticles encapsulating p53-encoding circular RNA (p53-CircRNA) with 96% efficiency, outperforming SM-102 in delivery and restoring p53 to 2.5-fold over controls. Combined with half-dose everolimus, this system induced near-complete tumor regression (98% inhibition) in orthotopic NSCLC models. Mechanistically, p53-CircRNA restore PTEN and suppress PI3K/AKT feedback, while everolimus directly inhibit mTOR, establishing coordinated PAM blockade. Furthermore, p53-CircRNA reverse everolimus-induced pro-survival autophagy, reducing ATG7 and LC3B-II levels by 80%, and redirect the response toward apoptotic cell death. This strategy not only enhance antitumor efficacy but also significantly mitigate everolimus-related hepatotoxicity. Our work establishes peptide-lipid–based p53-CircRNA delivery as a clinically viable approach to overcome PAM inhibitor resistance in p53-deficient cancers. Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance Biological sciences/Biotechnology/Gene delivery Full Text Additional Declarations There is NO Competing Interest. Supplementary Files NCSI20251116.pdf Supplementary Information for Peptide-lipid nanoparticle-mediated delivery of p53-circRNA synergizes with everolimus for dual suppression of PI3K/AKT/mTOR pathway 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8092851","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":549357468,"identity":"a69b115d-3a0f-4432-9735-44101f1fd593","order_by":0,"name":"Xing-Jie 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