Enhancing Safety and Efficacy of Senolytic Therapies with Advanced Controlled Release Strategies

Enhancing Safety and Efficacy of Senolytic Therapies with Advanced Controlled Release Strategies | 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 Enhancing Safety and Efficacy of Senolytic Therapies with Advanced Controlled Release Strategies Lino Ferreira, Vitor Francisco, Andreia Marques, David Sanfeliu-Redondo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5442026/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 elimination of senescent cells by senotherapeutic interventions is being evaluated in several clinical trials for the treatment of age-related diseases; however, these approaches present several limitations, including a low senotherapeutic index (i.e., the safety margin between the dose of the drug that produces a desired effect and the dose that produces unwanted side effects is relatively low) and, in some cases, concerns regarding their elimination. Here, we report a nanoparticle (NP) formulation selected from a library of 42 polymeric NP formulations that is biocompatible, fully degradable, and presents a senotherapeutic index at least 44 times greater than that observed for the soluble drug. The NP is endocytosed by both proliferative and senescent cells, but only in the latter is it degraded at a sufficient level in the endolysosome to release the encapsulated senotherapeutic drug, which can then cross a damaged endolysosomal membrane, reach the cell cytoplasm and induce apoptosis. Importantly, our results show that the release kinetics of the senotherapeutic drug from the NP affect its efficacy. We demonstrate the full potential of this formulation in the aged liver, particularly in the vascular compartment. The NP formulation, which is injected intravenously into naturally aged Wistar rats, accumulates significantly in the aged liver, reducing the senescence burden in the endothelial cell compartment. This contributes to decreases in portal pressure and liver fibrosis. Taken together, the strategy reported here increases the safety and efficacy of pharmacological interventions to treat age-related diseases. Biological sciences/Biotechnology/Nanobiotechnology/Nanoparticles Biological sciences/Chemical biology/Drug delivery Ageing Senescence Senotherapy Nanoparticles Liver microcirculation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supportinginformation.pdf Supporting information 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-5442026","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":387047543,"identity":"397eeeae-159d-4702-a658-f50be103bf16","order_by":0,"name":"Lino 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