Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-refractory primary brain tumors, with a median survival of less than 15 months despite the current standard of care combining surgical resection, radiotherapy, and temozolomide chemotherapy. A key driver of this poor prognosis is the tumor’s remarkable capacity to recurrence and sustain drug resistance — a process deeply rooted in pathways, including mutations in EGFR, NF-1, TERT PTEN genes and dysregulated of oncogenic signaling activation of PI3K/AKT/mTOR, RAS/MAPK, and Wnt/β-catenin. Understanding the chemical biology underpinning these pathways — from protein–protein interactions and post-translational modifications to epigenetic reprogramming — is essential for identifying vulnerabilities that can be therapeutically exploited. At the same time, the blood–brain barrier (BBB) presents a formidable pharmacokinetic obstacle, severely limiting the delivery of small molecules and biologics to the tumor microenvironment.

Nanotechnology offers a transformative platform to address these challenges simultaneously. Engineered nanoparticles — including lipid nanoparticles, polymeric carriers, inorganic nanostructures, and exosome-based systems — can be precisely functionalized to cross the BBB, target oncogenic cell populations, and deliver a diverse cargo of therapeutic agents, including small-molecule inhibitors, CRISPR/Cas9 gene-editing complexes, mRNA constructs, and siRNA sequences. This Research Topic aims to bring together cutting-edge research at the intersection of chemical biology and nanomedicine, fostering a multidisciplinary dialogue on how nanoparticle-based strategies can be rationally designed to interrogate and disrupt oncogenic signaling, reverse drug resistance mechanisms, and ultimately improve therapeutic outcomes in GBM.

This Research Topic welcomes original research articles, reviews, and perspective pieces covering, but not limited to, the following themes:

• Oncogenic signaling in GBM — molecular dissection of key pathways driving tumor progression, stemness, and therapeutic resistance
• Nanoparticle design and functionalization — synthesis, surface engineering, and BBB-targeting strategies for CNS delivery
• CRISPR/Cas9, mRNA, and siRNA delivery — nanoparticle-mediated gene editing and gene silencing approaches in GBM models
• Chemical biology tools — small-molecule probes, activity-based profiling, and chemoproteomics applied to GBM oncoproteins
• Drug resistance mechanisms — epigenetic, metabolic, and microenvironmental contributors to treatment failure
• Combination strategies — co-delivery systems integrating gene therapy with chemotherapy, immunotherapy, or radiotherapy
• Translational and preclinical models — in vitro, organoid, and in vivo GBM systems for evaluating nanoparticle efficacy and safety

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Chemical Biology Meets Nanomedicine: Nanoparticle Tools for Oncogenic Signaling and Drug Resistance in Glioblastoma