Overcoming barriers: mechanisms and strategies of nanoparticles in overcoming the blood-brain barrier and drug resistance in glioblastomas

Glioma, particularly glioblastoma (GBM), represent a major challenge in neuro-oncology due to their highly aggressive nature and poor therapeutic outcomes. The presence of the blood-brain barrier (BBB) severely restricts the efficient delivery of therapeutic agents to tumor sites, while the frequent emergence of drug resistance further compromises treatment efficacy.In recent years, nanoparticles have emerged as promising drug delivery platforms, demonstrating considerable potential in overcoming the BBB, enhancing targeting specificity, and reversing drug resistance, owing to their favorable biocompatibility and tunable physicochemical properties. This review provides a comprehensive overview of recent advances in the application of nanoparticles for glioma therapy, with a particular focus on strategies for BBB penetration and resistance reversal.Specifically, we summarize the design principles and functional modifications of nanoparticles, as well as their diverse therapeutic mechanisms, including drug delivery, photothermal and photodynamic therapy, ferroptosis induction, and modulation of the tumor microenvironment. In addition, the mechanisms underlying nanoparticle-mediated targeting and controlled drug release are discussed in detail.Importantly, current evidence suggests that nanoparticle-based platforms offer a versatile and effective approach for overcoming key biological barriers and therapeutic resistance in glioma, although their clinical translation remains constrained by challenges related to safety, scalability, and targeting heterogeneity. Future research should focus on the development of multifunctional and personalized nanomedicine strategies, integration with multimodal therapies, and rigorous evaluation of long-term safety and clinical efficacy, in order to facilitate the successful translation of these technologies into clinical practice.