Dual-ligand curcin-loaded hybrid solid lipid nanoparticles achieve durable gliosarcoma remission while preserving neuro-behavioral function

Rationale: Gliosarcoma (GSM) is a rare, highly invasive glioblastoma subtype with limited therapeutic options and a poor prognosis.We report the first dual-ligand hybrid solid lipid nanoparticle (HSLN) system for blood-brain barrier (BBB) penetration and targeted delivery of curcin, a type I ribosome-inactivating protein (RIP), to orthotopic GSM.Methods: HSLNs (~150-200 nm, polydispersity index (PDI) < 0.3, zeta potential () -8 mV) were co-functionalized with transferrin and RGD peptides at optimized 4:6 ratios to enhance BBB transcytosis and tumor uptake.Physicochemical, cytotoxicity, and docking studies assessed curcin stability, bioactivity, and multi-receptor interactions.In vivo biodistribution, proteomics, and therapeutic efficacy were evaluated in BALB/c-nu and ICR-nu orthotopic GSM models, with neurobehavioral assessments for functional preservation.Results: Intravenous curcin-loaded dual-ligand HSLNs achieved complete tumor regression in 60% of BALB/c-nu and 90% of ICR-nu mice, extending median survival from 14 to 38 days in BALB/c-nu mice and resulting in median survival not reached in an independent ICR-nu cohort.Neurobehavioral function was preserved during treatment.Biodistribution and proteomic analyses confirmed efficient BBB penetration, tumor-selective accumulation, and suppression of VEGFA/C, MMP-9, PDGFB, and SERPINE1.Molecular docking revealed strong binding of curcin to GSM-associated receptors (EGFR, EphA2, mGluR6,.Conclusions: Stoichiometry-optimized dual-ligand HSLNs enable targeted, BBB-penetrant delivery of curcin, achieving durable GSM remission with functional preservation.This theranostic-ready platform combines therapeutic potency with tumor specificity, offering a promising strategy for ribosome-inactivating protein delivery in GSM and other CNS malignancies.