Blood–Brain\nBarrier-Penetrative Fluorescent\nAnticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma\nTherapy

Currently\nused drugs for glioblastoma (GBM) treatments are ineffective,\nprimarily due to the significant challenges posed by strong drug resistance,\npoor blood–brain barrier (BBB) permeability, and the lack of\ntumor specificity. Here, we report two cationic fluorescent anticancer\nagents (TriPEX-ClO<sub>4</sub> and TriPEX-PF<sub>6</sub>) capable\nof BBB penetration for efficient GBM therapy via paraptosis and ferroptosis\ninduction. These aggregation-induced emission (AIE)-active agents\nspecifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated\nparaptosis and GPX4-mediated ferroptosis. Specifically, they rapidly\ninduce substantial mitochondria-derived vacuolation, accompanied by\nreactive oxygen species generation, decreased mitochondrial membrane\npotential, and intracellular Ca<sup>2+</sup> overload, thereby disrupting\nmetabolisms and inducing nonapoptotic cell death. In vivo imaging\nrevealed that TriPEX-ClO<sub>4</sub> and TriPEX-PF<sub>6</sub> successfully\ntraversed the BBB to target orthotopic glioma and initiated effective\nsynergistic therapy postintravenous injection. Our AIE drugs emerged\nas the pioneering paraptosis inducers against drug-resistant GBM,\nsignificantly extending survival up to 40 days compared to Temozolomide\n(20 days) in drug-resistant GBM-bearing mice. These compelling results\nopen up new venues for the development of fluorescent anticancer drugs\nand innovative treatments for brain diseases.