Peptide-mediated nanotheranostics for glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, with limited therapeutic efficacy and poor clinical outcomes. A major obstacle to effective treatment and molecular imaging is the blood-brain barrier (BBB), which severely restricts the delivery of therapeutic agents and imaging probes to the tumor microenvironment. BBB-penetrating and tumor-targeting peptides have emerged as versatile molecular platforms that can facilitate BBB transport, enhance tumor accumulation, and improve the delivery of therapeutic and diagnostic cargos. This review provides a comprehensive overview of the development of BBB-penetrating and GBM-targeting peptides, focusing on their sources, screening strategies, and underlying transport mechanisms. Representative peptides, including Angiopep-2, mApoE, T7, RVG, cRGD, and iRGD, are discussed in the context of drug delivery and molecular imaging applications. Recent advances in artificial intelligence and machine-learning approaches are highlighted as complementary strategies for accelerating peptide discovery and optimizing candidate selection, while emphasizing the necessity of experimental validation. Preclinical studies demonstrate that peptide functionalization can improve BBB permeability, tumor targeting, intratumoral distribution, and imaging performance in various delivery systems. Early clinical translation has been explored through peptide–drug conjugates, chlorotoxin-based imaging agents and cellular therapies, RGD-based radiotracers, and peptide vaccines; however, clinical evidence remains preliminary and variable across platforms. Key challenges limiting broader application include peptide instability, receptor heterogeneity, off-target clearance, protein-corona formation, and formulation-dependent biological performance. Overall, peptide-mediated delivery and nanotheranostics platforms represent a promising strategy to overcome BBB limitations and advance precision diagnosis and treatment of GBM. Future progress will require integrated optimization of peptide engineering, delivery systems, imaging technologies, and rigorous clinical validation to achieve reliable and scalable translation.