Recent Advances in Nanoparticle-Based Strategies for Overcoming Hypoxia in Glioblastoma Photodynamic Therapy

Glioblastoma (GBM) remains one of the most aggressive primary brain tumours, and its hypoxic microenvironment represents a major barrier to effective photodynamic therapy (PDT). Reduced oxygen availability limits reactive oxygen species generation, while oxygen consumption during PDT may further aggravate tumour hypoxia and promote adaptive mechanisms associated with treatment resistance. A literature search covering January 2024 to August 2026 was conducted in PubMed, Scopus, and Web of Science using the Boolean query “PDT AND nanoparticles”. Original experimental studies investigating nanoparticle-based PDT in glioblastoma, with particular emphasis on strategies addressing hypoxia-related limitations, were considered eligible. Twelve studies were included in the qualitative synthesis and critically evaluated in terms of oxygen-modulating strategies, preservation of photodynamic activity under hypoxic conditions, therapeutic efficacy, and biosafety. The analysed nanoplatforms employ two principal strategies: direct alleviation of tumour hypoxia through local oxygen generation and partial circumvention of oxygen dependence through photochemical mechanisms that remain effective under reduced oxygen availability. Catalytic components including Pt, MnO2 and Fe3O4@BiFeO3 enable the conversion of endogenous H2O2 into oxygen, whereas type I photodynamic reactions provide an alternative means of maintaining ROS generation under hypoxic conditions. Beyond hypoxia modulation, multifunctional nanoplatforms integrate PDT with complementary therapeutic mechanisms, including photothermal therapy, redox disruption, ferroptosis, targeted protein degradation using PROTACs and immunomodulation. Several systems have demonstrated promising antitumour activity in experimental GBM models together with favourable preliminary biosafety profiles. However, substantial heterogeneity in experimental models, administration routes and irradiation protocols, as well as unresolved issues concerning long-term safety, blood–brain barrier penetration and clinical translation, remain important challenges. Overall, multifunctional nanoplatforms capable of modulating tumour hypoxia while simultaneously targeting additional mechanisms of GBM resistance represent a promising direction for the further development of PDT.