A transferrin receptor-targeted liposome for iron metabolism regulation-augmented photodynamic therapy in glioblastoma.

The clinical standard treatments for glioblastoma (GBM) present a therapeutic challenge of high recurrence. 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) offers a promising alternative owing to the selective biosynthesis of protoporphyrin IX (PpIX) in tumor mitochondria with favorable phototoxicity. However, the highly elevated iron metabolism leads to low biosynthetic efficiency and insufficient accumulation of PpIX, thus limiting the PDT efficacy. Here, we developed a transferrin receptor (TfR)-targeted liposome (AD@LST) that co-delivers 5-ALA and the iron chelator deferoxamine (DFO) for tumor-targeted PpIX biosynthesis and augmented PDT in GBM. AD@LST can efficiently penetrate the blood-brain barrier, and achieve tumor-selective delivery through TfR-mediated uptake and glutathione-responsive drug release. DFO chelates iron ions to downregulate ferrochelatase expression, while concurrently upregulating coproporphyrinogen oxidase and aminolevulinic acid synthase 1 expression, thereby increasing PpIX above physiological concentration (2.54-fold enhancement) in orthotopic GBM. Furthermore, iron deprivation by AD@LST counteracts heme-mediated antioxidant defenses and reduces mitochondrial oxygen consumption, markedly further improving PDT efficacy. In subcutaneous GBM models, AD@LST enables fluorescence imaging-guided repeated PDT with efficient tumor suppression. This liposome demonstrates great potential in clinical translational applicability.