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Although mRNA therapies have shown promise in addressing central nervous system (CNS) disorders, the successful delivery of mRNA therapeutics to the nervous system is still hindered by many biological barriers. In this study, it is demonstrated that, compared with commercial MC3 lipid nanoparticles (MC3 LNPs), mRNA\u2010loaded P6CIT\u2010derived lipopolymer nanoparticles (P6CIT LPNPs), which are delivered via intrathecal injection, achieve effective penetration through the pia mater. More importantly, this P6CIT LPNP demonstrates the ability to achieve highly targeted mRNA transfection in gliocytes within the spinal cord and dorsal root ganglia (DRG), which is essential for the regulation of neuroinflammation. Furthermore, two intrathecal injections of P6CIT LPNPs encapsulating mIL\u201010 (P6CIT\/mIL\u201010) significantly alleviate PIPN by reducing proinflammatory cytokine production, gliocyte activation, and presynaptic NMDA receptor hyperactivity in both male and female mice. This study presents a promising and clinically translatable platform for using mRNA\u2010loaded LPNPs to treat PIPN.<\/jats:p>","DOI":"10.1002\/advs.202500362","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:40:15Z","timestamp":1747190415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pia Mater\u2010Penetrable Lipopolymer Nanoparticles for Gliocyte\u2010Targeted IL\u201010 mRNA Therapy Alleviate Paclitaxel\u2010Induced Peripheral Neuropathy"],"prefix":"10.1002","volume":"12","author":[{"given":"Xinrou","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510000 China"},{"name":"Nanhai Translational Innovation Center of Precision Immunology Sun Yat\u2010Sen Memorial Hospital  Foshan 528200 China"},{"name":"Department of Anesthesiology Sun Yat\u2010Sen Memorial Hospital 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