Nanosensitizer-based energy therapies for glioblastoma: A systematic review of a four-generation paradigm in evolving strategies (2020-2025).

In oncology, glioblastoma multiforme (GBM) is considered a crucial challenge due to rapid drug resistance and the protective effects of the blood-brain barrier (BBB). Photodynamic therapy (PDT), photothermal therapy (PTT), and sonodynamic therapy (SDT) have emerged as promising approaches for GBM treatment, while limited energy penetration through the skull can restrict their effectiveness in intracranial tumors. The present systematic review aimed to evaluate studies on nanoparticle-based PDT, PTT, and SDT using online databases, including PubMed, Scopus, Web of Science, and Embase, from 2020 to 2025. Non-English studies, reviews, abstracts, book chapters, and retracted papers were excluded. A total of 663 records were initially identified, and 47 studies met the inclusion criteria. Based on the analysis of these studies, we observed a progressive shift in therapeutic strategies, categorized into four generations: (1) surface-limited ablation using near-infrared (NIR)-I thermal cytotoxicity; (2) multimodal synergistic therapies; (3) stimuli-responsive switch-on systems; and (4) deep-penetration modalities. The fourth generation is characterized by technologies, such as NIR-II lasers, X-ray-induced photodynamic therapy (X-PDT), low-intensity ultrasound (LIUS) and focused ultrasound, to overcome the depth barrier and promote immunogenic cell death. Nanoparticle-based GBM therapies are increasingly shifting toward multifunctional, BBB-targeted, and immune-engaging platforms. This trend highlights the need for multimodal, standardized, safe, and simpler designs.