Metalloporphyrin organic framework oxygen-generators enable tumour-targeted photodynamic therapy and metabolic reprogramming for enhanced glioblastoma treatment.

Glioblastoma (GBM) is one of the most lethal types of brain tumours. Photodynamic therapy (PDT) may prove noteworthy for treating GBM due to its superior biocompatibility and spatio-temporal selectivity. However, its effectiveness is severely limited by insufficient singlet oxygen (1O2) generation and tumour hypoxia. Herein, we developed a Pt@PCN-222(Mn)-PEG nanostructure incorporating Mn3+ and porphyrin (TCPP)-coordinated metal organic frameworks (MOFs), co-loaded with platinum (Pt) nanoparticles and surface-modified with polyethylene glycol (PEG). The sub-100 nm size of the Pt@PCN-222(Mn)-PEG nanostructure facilitates effective blood brain barrier penetration and accumulation in GBM due to their enhanced permeability and retention effect. Coordination of Mn3+ within the TCPP macrocycle of the MOF shell induces a 33 % reduction in TCPP phosphorescence, thereby enhancing triplet state (T1) oxygen (O2) quenching and increasing 1O2 generation by 1.5-fold. Within the tumour microenvironment, Mn3+ depletes glutathione and reduces to Mn2+, which amplifies the TCPP-mediated PDT effect by preventing 1O2 scavenging. Furthermore, Pt nanoparticles catalyse the conversion of hydrogen peroxide to O2, enhancing O2-dependent PDT efficacy. The increased O2 levels promote the degradation of hypoxia-inducible factor 1-alpha (HIF-1α), resulting in the inhibition of the PI3K/AKT/HIF-1α signalling pathway. These results indicate the down-regulation of genes related to glucose metabolism, thus, disrupting cellular energy metabolism and ultimately inducing GBM cell death due to energy metabolic collapse.