CNS Precision Targeting: Glycyrrhizin-Valproic Acid Liposomal Therapy as a Breakthrough for Drug-Resistant Epilepsy

Introduction: Drug-resistant epilepsy (DRE) is a major therapeutic challenge, largely driven by neuroinflammation mediated by activated microglia. Valproic acid (VPA), while widely used, is limited by poor targeting and pro-inflammatory effects. Glycyrrhizin, a natural HMGB1 lig-and with anti-inflammatory properties, offers potential for targeted microglial modulation. Methods: Glycyrrhizin-decorated VPA-loaded liposomes were developed using the thin-film hydra-tion technique. The formulations were characterized for particle size, zeta potential, encapsulation efficiency, and morphology. In vitro studies in BV2 and HMC3 microglial cells assessed drug release, uptake, cytotoxicity, nitric oxide (NO) production, cytokine levels (TNF-α, IL-6, IL-1β), and gene expression (iNOS, COX-2). In vivo efficacy was evaluated in a PTZ-induced epilepsy mouse model, with immunohistochemistry confirming neuroinflammatory changes. Stability was further assessed under ICH guidelines. Results: Optimized glycyrrhizin-functionalized liposomes (150 nm, EE 85%) demonstrated sustained drug release and stability. In vitro, they significantly suppressed NO and pro-inflammatory cytokine levels, downregulated iNOS and COX-2, and improved cell viability compared with free VPA or uncoated liposomes (p < 0.001). In vivo, they reduced microglial activation and neuroinflammation more effectively than controls (p < 0.01–0.001). Accelerated stability testing confirmed retention of physicochemical properties under standard storage conditions Discussion: Glycyrrhizin functionalization enhanced VPA’s anti-inflammatory and neuroprotective effects by enabling targeted delivery to activated microglia. This approach mitigated both the inflam-matory response and cytotoxicity associated with free VPA, suggesting synergistic therapeutic bene-fits. Conclusion: Glycyrrhizin-decorated VPA liposomes represent a promising precision-targeted nanocarrier for controlling neuroinflammation in DRE. Further pharmacokinetic and clinical evalua-tions are warranted to establish their translational potential.