Journal Article

Pia Mater‐Penetrable Lipopolymer Nanoparticles for Gliocyte‐Targeted IL‐10 mRNA Therapy Alleviate Paclitaxel‐Induced Peripheral Neuropathy

Wang, Hongjin, Li, Chenguang, Li, Xiangpen, Lu, Hengjian, Peng, Ying, Tang, Yingsen, Chen, Jinjin, Wei, Lingyu, Lin, Xinrou, Wang, Hongxuan, Zeng, Ling

2025

Overview

Paclitaxel (PTX) is a commonly used chemotherapeutic agent for treating various solid tumors; however, it often leads to a severe side effect known as paclitaxel‐induced peripheral neuropathy (PIPN), for which effective treatments are limited. 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‐loaded P6CIT‐derived 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‐10 (P6CIT/mIL‐10) 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‐loaded LPNPs to treat PIPN. The P6CIT lipopolymer demonstrates superior transfection efficacy in the spinal cord and DRG, as well as enhanced penetration of the pia mater compared to the MC3 ionizable lipid. Intrathecal delivery of P6CIT LPNPs enables effective transfection in the gliocytes in the spinal cord and DRG. Notably, intrathecal administration of P6CIT/mIL‐10 significantly alleviates allodynia in paclitaxel‐induced peripheral neuropathy mice.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / dorsal root ganglion / Female / Ganglia, Spinal - metabolism / Gene expression / IL‐10 / Interleukin-10 - genetics / Interleukin-10 - metabolism / lipopolymer nanoparticle / Male / Mice / Microscopy / mRNA / Nanoparticles / Nanoparticles - chemistry / Neuroglia - metabolism / Paclitaxel - adverse effects / paclitaxel‐induced peripheral neuropathy / Peripheral Nervous System Diseases - chemically induced / Peripheral Nervous System Diseases - drug therapy / Peripheral Nervous System Diseases - therapy / Peripheral neuropathy / Permeability / Proteins / RNA, Messenger - administration & dosage / RNA, Messenger - genetics / Spinal cord