Designed Liquid Crystalline Nanoassemblies From Clinically Validated Polyunsaturated Lipids for Combined Antioxidant, Anti-Apoptotic, and Neurotrophic Treatments

Neurodegenerative diseases present a significant challenge in modern medicine, largely due to the interplay of oxidative stress, Apoptosis, and neuroinflammation. The development of advanced Materials capable of simultaneously regulating multiple pathological processes is a critical unmet need. Here, we introduce ionizable pH-responsive lyotropic liquid crystalline nanocarriers as a promising self-assembled materials-based solution for neuroregeneration. We engineered non-lamellar polyunsaturated (DLin-MC3-DMA)-based lipid nanoassemblies with a unique combination of antioxidant, anti-apoptotic, and neurotrophic functionalities. By incorporating a multi-targeted phytochemical blend (quercetin, ginkgolides B and C, and kaempferol), the lipid-based nanomedicines effectively suppress inflammatory mediators (IL-1β, NF-κB, and JNK1/2) and stimulate endogenous antioxidant defenses via NRF2/ARE activation. The mechanistic involvement of the mTOR/Akt/BDNF/GSK3β pathway was examined to assess the in vitro therapeutic potential of the antioxidant‑loaded lipid nanoparticles (LNPs). The designed assemblies activate pro‑survival (p‑AKT/mTOR) and neurotrophic (BDNF) signaling pathways while preserving mitochondrial integrity in a cellular neurodegeneration model. The ionizable nature of DLin‑MC3‑DMA imparts pH‑responsiveness to the LNPs, driving a progressive enrichment of the inverted hexagonal (H_II) phase under acidic conditions. This structural transition enables precise intracellular drug release, thereby enhancing therapeutic efficacy. Building on this, LNP‑mediated regeneration enables the development of next generation neurotherapeutic platforms by simultaneously targeting oxidative stress, inflammation, and key neurotrophic pathways.

SAXS; ginkgolide B; ginkgolide C; hexosomes; ionizable omega‐6 polyunsaturated lipid; kaempferol; lipid nanoparticles (LNPs); mitochondrial oxidative stress; multi‐target antioxidants; pH‐responsive structures.