Combating Blood–Brain Barrier Limitations and Drug Resistance in Glioblastoma Using Lipid Nanoparticle-Based Drug Delivery.

Background: Brain tumors, especially glioblastoma multiforme(GBM), continue to be one of the deadliest cancers, with a median survival rate of 12 to 15 months. The blood-brain barrier (BBB) and drug resistance through multiple mechanisms — primarily P-glycoprotein efflux, MGMT-mediated DNA repair, and the adaptability of cancer stem cells —greatly hinder the effectiveness of standard chemotherapy, such as temozolomide (TMZ). Objective: This assessment examines lipid nanoparticle (LNP) approaches—such as solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, and ionizable LNPs—as targeted delivery mechanisms to surmount the BBB and drug resistance in brain tumors. Result: Surface-modified NLCs with polyunsaturated fatty acid ligands (ALA, GLA) demonstrated BBB permeability (Papp ~1.9 × 10⁻³ cm/s) and resulted in up to 13.9-fold decreases in IC50 for patient-derived GBM cells compared to the free drug. Receptor-targeted LNPs (transferrin, anti-EGFR) achieved 3–5 times greater intracranial drug concentrations in orthotopic rodent models. The co-encapsulation of TMZ alongside P-gp inhibitors or the silencing of MGMT/BCL-2 using siRNA restored chemoresistance by 60 80%. LNPs that respond to stimuli and utilize the tumor's acidic microenvironment allowed for regulated drug release, reducing off-target toxicity. Conclusion:LNPs provide a versatile, biocompatible solution for achieving concurrent BBB traversal and multi-target resistance reversal in brain tumors LNP with PUFA also should dual action drug delivery in treating brain tumor. Innovations in surface engineering, co-delivery, and stimuli-responsive design offer significant potential for personalized, low-toxicity neuro-oncology treatments, contingent on scalable production and clinical validation