Journal Article

Methylprednisolone substituted lipid nanoparticles deliver C3 transferase mRNA for combined treatment of spinal cord injury

Ma, Haiqiang, Cai, Shiyi, Li, Jianfeng, Su, Lili, Dong, Haoru, Xie, Rong, He, Zongxing, Yang, Huiying

2025

Overview

Spinal cord injury (SCI), characterized by the disruption of neural pathways and an increase in inflammatory cell infiltration, leads to profound and lasting neurological deficits, with a high risk of resulting in permanent disability. Currently, the therapeutic landscape for SCI is notably sparse, with limited effective treatment options available. Methylprednisolone (MP), a widely used clinical anti-inflammatory agent for SCI, requires administration in high doses that are associated with significant adverse effects. In this study, we introduce an innovative approach by substituting cholesterol with MP to engineer a novel Lipid Nanoparticle (MP-LNP). This strategy aims to enhance the localization and concentration of MP at the injury site, thereby amplifying its therapeutic efficacy while mitigating systemic side effects. Furthermore, we explore the integration of C3 transferase mRNA into MP-LNPs. C3 transferase, a potent inhibitor of the RhoA pathway, has shown promise in facilitating neurological recovery in animal models of SCI and is currently being evaluated in clinical trials. The novel formulation, MP-LNP-C3, is designed for direct administration to the injury site during decompression surgery, offering a targeted therapeutic modality for SCI. Our findings reveal several significant advantages of this approach: Firstly, the incorporation of C3 transferase mRNA into MP-LNPs does not compromise the structural integrity of the nanoparticles, ensuring efficient mRNA expression within the spinal cord. Secondly, the MP-LNP formulation effectively attenuates inflammation and reduces the adverse effects associated with high-dose MP treatment in the acute phase of SCI. Lastly, MP-LNP-C3 demonstrates notable neuroprotective properties and promotes enhanced recovery of motor function in SCI mouse models. Together, these results underscore the potential of this innovative LNP-based therapy as a promising avenue for advancing the treatment of clinical SCI. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Advanced Non-viral Delivery Systems in Tissue Engineering / Animal models / Animals / Anti-inflammation / Anti-inflammatory agents / Anti-Inflammatory Agents - pharmacology / Biotechnology / C3 transferase / Chemical properties / Chemistry / Chemistry and Materials Science / Cholesterol / Clinical trials / Combined treatment / Cytokines / Decompression / Disease Models, Animal / Dosage and administration / Drug delivery systems / Drug dosages / Drug therapy / Drugs / Effectiveness / Efficiency / Gene expression / Health aspects / Inflammation / Kinases / Lipids / Lipids - chemistry / Liposomes / LNP / Messenger RNA / Methylprednisolone / Methylprednisolone - chemistry / Methylprednisolone - pharmacology / Mice / Molecular Medicine / Nanoparticles / Nanoparticles - chemistry / Nanotechnology / Neurological diseases / Neuroprotection / Pharmaceutical research / Polyethylene glycol / Proteins / Recovery / RhoA protein / RNA, Messenger - genetics / Side effects / Spinal cord injuries / Spinal Cord Injuries - drug therapy / Spinal Cord Injuries - therapy / Spinal cord injury / Structural integrity / Transferases / Transmission electron microscopy / Tumor necrosis factor-TNF / Vehicles