Beyond Efficacy: Preclinical Validation and Translational Readiness of Recent Multimodal Photodynamic Nanoplatforms for Glioblastoma

Multimodal photodynamic therapy (PDT)-based nanoplatforms are increasingly being developed for glioblastoma (GBM) to improve photosensitizer delivery, overcome tumor hypoxia, and combine PDT with complementary therapeutic mechanisms. However, promising antitumor activity does not necessarily translate into adequate preclinical validation or clinical readiness. This review critically evaluates recent studies published between January 2025 and August 2026, identified through PubMed, Scopus and Web of Science. Of 3617 records screened, 35 studies met the broader eligibility criteria for nanoparticle-mediated PDT in GBM, including 19 studies incorporating in vivo evaluation. Particular attention was given to the biological relevance of experimental models, survival assessment, biodistribution, pharmacokinetics, clearance, systemic and neurological safety, and platform-specific translational limitations. Orthotopic models were used in 16 of 19 in vivo studies, whereas immunocompetent and immunodeficient hosts were represented almost equally. Nevertheless, clinically challenging settings such as post-resection disease, acquired temozolomide resistance and recurrence after standard therapy were rarely reproduced. Quantitative pharmacokinetic and elimination data were limited, and fluorescence or elemental measurements frequently reflected individual platform components rather than intact nanostructures. Safety assessments were predominantly short-term and often focused on body weight, routine blood parameters and organ histology. Overall, the current evidence demonstrates substantial therapeutic innovation but also reveals a persistent gap between antitumor efficacy and translational validation. Future studies should prioritize clinically representative models, quantitative absorption, distribution, metabolism and excretion (ADME) characterization, long-term and neurological safety assessment, and comparisons with current standard-of-care treatment.