Abstract
ABSTRACT
Glioblastoma (GBM) remains one of the most lethal malignancies because durable tumor control is constrained by limited brain‐tumor drug exposure, metabolic plasticity, stem‐like tumor states, and an immunosuppressive microenvironment. We developed apolipoprotein B fragment‐decorated nanoparticles co‐loaded with regorafenib and erythrodiol (ApoBf‐R/E@NPs), a low‐density lipoprotein receptor‐oriented biomimetic nanoplatform that couples brain‐tumor delivery with coordinated dual‐drug exposure. Fixed‐ratio combination‐index analysis demonstrated synergy between the two agents. Regorafenib disrupts autophagy‐associated nutrient salvage and restricts angiogenic support, whereas erythrodiol stabilizes ATP‐binding cassette transporter A1 and depletes cellular cholesterol. These complementary perturbations converge on ATP depletion, mitochondrial dysfunction, and suppression of phosphoinositide 3‐kinase/protein kinase B and mitogen‐activated protein kinase signaling. Across established and patient‐derived GBM models, treatment broadly impaired tumor‐cell survival while suppressing stemness‐associated programs and reducing viability and tumorsphere persistence in patient‐derived glioma stem‐like cell cultures. Treatment also promoted an immunogenic cell death‐associated tumor‐cell state and antitumor immune remodeling. In immunocompetent GBM models, ApoBf‐R/E@NPs showed preferential intracranial tumor‐associated delivery, suppressed orthotopic and untreated distal tumor growth, and delayed postoperative regrowth, accompanied by systemic immune remodeling and expansion of memory‐associated T‐cell populations. These findings establish a blood‐brain barrier‐oriented nanodelivery strategy that couples complementary metabolic vulnerabilities to broad GBM control, stem‐like compartment suppression, and antitumor immunity.