Study Design <p>Animal study.</p> Objectives <p>The NLRP3 inflammasome is a key mediator in secondary cascade of spinal cord injury (SCI), making it a potential therapeutic target. This study aimed to develop a nanoformulated version of fingolimod and investigate its effects on neuroinflammation, NLRP3 inflammasome activity, glial activation, lesion volume, and functional outcomes in a rat model of moderate contusive SCI.</p> Setting <p>Experimental animal research laboratory, AlSafwa University College, Karbala, Iraq.</p> Methods <p>Fingolimod-loaded PLGA nanoparticles were synthesized using the emulsion solvent evaporation method and characterized for size, morphology, and drug release. Adult male Wistar rats underwent a standardized contusion SCI at T9 and were randomized into three groups (<i>n</i> = 13): Sham, SCI + Vehicle, and SCI + Nano-Fingolimod (10 ng/ml). Behavioral assessments using the BBB locomotor test were performed on days 1, 3, 5, 7, 10, 12, and 14 post-injuries. Histological analysis quantified lesion volume and inflammatory cell infiltration. Immunofluorescence (IF) and Western blotting were used to evaluate the expression of NLRP3, ASC, cleaved caspase-1, IL-1β, GFAP, and Iba-1.</p> Results <p>Nano-fingolimod significantly improved BBB locomotor scores compared to the SCI group (<i>p</i> &lt; 0.0001), indicating enhanced motor recovery. Histological examination revealed reduced lesion volume and inflammatory cell density in the treatment group. IF and Western blot analyses showed marked suppression of NLRP3 inflammasome signaling components (NLRP3, ASC, cleaved caspase-1, and IL-1β) and reduced glial activation (GFAP, Iba-1).</p> Conclusion <p>Nanoformulated fingolimod provides neuroprotection and improves functional recovery after SCI by attenuating NLRP3 inflammasome activation and glial reactivity. Targeted nanodelivery enhances its CNS bioavailability and reduces toxicity, positioning it as a promising candidate for SCI therapy.</p> Sponsorship <p>None.</p> <p></p>