A Hybrid-Targeting Nanoparticle for Penetrable Delivery of Temozolomide to Enhance Glioblastoma Therapy

Chemotherapy for glioblastoma (GBM) has not achieved the desired outcome due to inefficient blood-brain barrier (BBB) penetration and limited tumor-specific drug accumulation. Strategies that employ bioinspired nanoparticles to enhance targeted drug accumulation can help improve therapeutic efficacy. In this work, a novel nanoparticle, PCM@TMA-lip, exhibiting hybrid-targeting capabilities, is presented, with an engineered cell membrane coated on a lipid core. The membrane modified with a biologically derived peptide enables PCM@TMA-lip to evade immune clearance and enable precise tumor targeting. The lipid core with docosahexaenoic acid (DHA)-conjugated Temozolomide (TMZ) enhances FABP7-mediated uptake, promotes lysosomal escape via lipid peroxidation, and reduces tumor migration and drug resistance. In vitro, PCM@TMA-lip inhibited tumor cell malignancy and suppressed the growth of 3D spheroids. In vivo, it suppressed tumor progression, reduced Ki67⁺ proliferation, increased TUNEL⁺ apoptosis, and prolonged survival in GBM-bearing mice, highlighting its potential as an effective strategy to improve GBM chemotherapy.