Heparin-Pullulan Liposomal Nano-gel of Silymarin: Overcoming the Blood-Brain Barrier for Dementia Therapy; Characterization, In Vivo Evaluation, and Histopathological Studies

Background/Objectives: Dementia remains one of the major global health challenges of the modern era. Researchers worldwide continue to seek effective therapeutic strategies to combat this neurodegenerative condition. Silymarin, a natural compound with strong neuroprotective and antioxidant properties, holds great potential for dementia management; however, its poor aqueous solubility and limited ability to cross the blood–brain barrier (BBB) have restricted its clinical use. This study focused on the formulation and evaluation of a heparin–pullulan silymarin liposomal nano-gel (HPSL) to enhance silymarin’s bioavailability and brain delivery. Methods: The HPSL nano-gel was synthesized using the thin-film hydration technique and optimized based on entrapment efficiency, particle size, zeta potential, and in-vitro release kinetics. Neuroprotective efficacy of HPSL nano-gel was assessed in mice through behavioral evaluations, biochemical estimation of oxidative stress, analysis of cholinergic enzyme activity and histopathological examination of brain tissues. Results: Morphological characterization using scanning electron microscopy (SEM) confirmed uniform nanoscale structure. The optimized formulation (HPSL-3) exhibited a particle size of 406.07 ± 19.33 nm, zeta potential of –23.72 ± 7.64 mV, and entrapment efficiency of 73.53 ± 12.05%, indicating good stability and efficient drug loading. The in-vitro release followed non-Fickian diffusion, suggesting a sustained drug-release profile. Behavioral studies in scopolamine-induced amnesic mice (elevated plus maze, hole board, and light/dark paradigms) demonstrated significant (p ≤ 0.001) improvements in learning and memory retention. Biochemical analyses revealed elevated levels of ChAT, SOD, CAT, and GSH, along with reduced AChE and MDA levels, supporting the formulation’s neuroprotective potential. Histopathological evaluation showed marked attenuation of neuronal degeneration, inflammation, and edema (HAI = 4) compared to the scopolamine group (HAI = 11). Conclusions: Overall, the HPSL formulation effectively enhanced silymarin delivery across the BBB, providing potent antioxidant, neuroprotective, and cholinergic modulatory effects. These findings suggest that HPSL represents a promising nano-carrier system for the treatment of dementia and other oxidative stress–related neurological disorders.