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Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disease with no cure to date. Therapeutic agents used to treat ALS are very limited, although combined therapies may offer a more effective treatment strategy. Herein, we have studied the potential of nanomedicine to prepare a single platform based on mesoporous silica nanoparticles (MSNs) for the treatment of an ALS animal model with a cocktail of agents such as leptin (neuroprotective) and pioglitazone (anti-inflammatory), which have already demonstrated promising therapeutic ability in other neurodegenerative diseases. Our goal is to study the potential of functionalized mesoporous materials as therapeutic agents against ALS using MSNs as nanocarriers for the proposed drug cocktail leptin/pioglitazone ( MSN-LEP-PIO ). The nanostructured materials have been characterized by different techniques, which confirmed the incorporation of both agents in the nanosystem. Subsequently, the effect, in vivo , of the proposed drug cocktail, MSN-LEP-PIO , was used in the murine model of TDP-43 proteinopathy (TDP-43 A315T mice). Body weight loss was studied, and using the rotarod test, motor performance was assessed, observing a continuous reduction in body weight and motor coordination in TDP-43 A315T mice and wild-type (WT) mice. Nevertheless, the disease progression was slower and showed significant improvements in motor performance, indicating that TDP-43 A315T mice treated with MSN-LEP-PIO seem to have less energy demand in the late stage of the symptoms of ALS. Collectively, these results seem to indicate the efficiency of the systems in vivo and the usefulness of their use in neurodegenerative models, including ALS.