Two primary symptom-relief drugs currently used to treat ALS patients are riluzole and edaravone. Riluzule acts as an NMDAR antagonist and edaravone functions as a scavenger of reactive oxygen species[68]. However, there remains an urgent need to develop effective disease-modifying therapies. Repurposing clinically available, FDA-approved drugs with known safety profiles and minimal organ toxicity, such as dantrolene, offers a promising strategy to accelerate clinical translation. This new formulation of dantrolene, Ryanodex, consists of crystalline nanoparticles[70]. While Ryanodex is FDA-approved for the treatment of malignant hyperthermia, its current application is intravenous, not intranasal[70]. A prior study failed to demonstrate efficacy of dantrolene in the same SOD1-G93A model[60], most likely due to its limited ability to cross the blood-brain barrier (BBB)[71]. Intranasal delivery of drugs, particularly in nanoparticle forms, has been well established to enhance BBB penetration, increasing drug concentration in the CNS and its retention time, thereby improving therapeutic efficacy while minimizing peripheral side effects and organ toxicity. This strategy is especially advantageous for treatment of long-term conditions, such as those involving chronic neurological diseases[72]. In fact, intranasal administration of riluzole nanoemulsions has been shown to produce higher brain concentrations than standard oral administration, enhancing its therapeutic potential in ALS[73]. Consistently, our previous studies demonstrated that intranasal administration of dantrolene nanoparticles in the Ryanodex formulation significantly increased brain concentration, prolonged drug duration, and enhanced the brain-to-blood concentration ratio compared to oral or subcutaneous administrations[62-64]. Intranasal dantrolene nanoparticles administered at the same dose (5mg/kg), daily, 5 days per week for up to 12 months, significantly inhibited memory loss in the 5XFAD Alzheimer’s disease mouse model, Discussion This study has demonstrated that intranasal dantrolene nanoparticles provide robust and significant therapeutic effects against motor neuron dysfunction, motor without evidence of side effects or nasal/liver toxicity[63, 74]. Given the chronic nature of ALS, the low systemic toxicity and high CNS penetration of intranasal dantrolene nanoparticle treatment further favor its utility for long-term treatment. In comparison with prior studies, the robust and significant neuroprotective and muscle-preserving effects observed in SOD1-G93A mice suggest enhanced drug delivery to the brain and spinal cord, with promoted efficacy in the CNS. Moreover, because ALS patients frequently develop difficult swallowing, intranasal drug delivery may be a more convenient and patient-friendly route of administration. A significant proportion of ALS patients develop cognitive impairment and depression-related psychiatric symptoms[75]. Accordingly, as intranasal dantrolene nanoparticles have demonstrated efficacy in treating memory dysfunction[63] and depressionand anxiety-like behaviors[76], this approach may offer additional clinical benefit beyond motor function preservation in the treatment of ALS. Similar to our previous findings in 5XFAD mice[63], the intranasal administration of vehicle alone (only the Ryanodex formulation) demonstrated predominantly minor, non-significant trends towards improvement in motor function, balance, and muscle strength, but to a clearly less effective degree than dantrolene-loaded nanoparticles. This suggests that dantrolene is the primary active agent providing neuroprotection and preserving muscle, although the potential additive role of the vehicle alone warrants further investigation. Although dantrolene is typically considered a muscle relaxant, it was not observed to impair 5XFAD mice[63]. In this ALS model, it significantly reversed muscle weakness, likely due to its motor neuron protection, causing reduced muscle denervation and potential direct protection against muscle damage. Overall, this preclinical study strongly supports the need for urgent clinical trials to evaluate the therapeutic potential of intranasal dantrolene nanoparticles in ALS patients.