Five-in-One NIR-II Phototheranostic Nanomedicine for Glioblastoma Multiforme: Unlock Bio-Barriers and Photothermal-Ferroptotic Amplification

Glioblastoma multiforme (GBM) remains difficult to treat due to complex biological barriers and a high rate of recurrence. Near-infrared II (NIR-II) phototheranostic nanomedicine, which offers superior tissue penetration depth and enhanced photothermal effects, has emerged as a a promising approach for GBM theranostics. In this study, we first propose a molecular design strategy that introduces expanded free space within aggregates to enhance nonradiative decay and maximize the photothermal efficacy (PCE). Building on this, we developed a holo-transferrin (holo-Tf)-based nanomedicine incorporating the designed phototheranostic molecules. This platform enables efficient blood-brain barrier (BBB) penetration via transferrin receptor (TfR)-mediated transcytosis and targeted delivery to tumor. Under 808 nm laser irradiation, this nanomedicine facilitates precise photothermal therapy (PTT) while simultaneously inducing ferroptosis. This dual action synergistically improves therapeutic outcomes by suppressing of heat shock proteins (HSPs) through ferroptosis. Overall, we developed a one-step self-assembled nanomedicine that integrates five functions: BBB penetration, tumor targeting, fluorescence imaging (FLI), photothermal imaging (PTI), and photothermal-ferroptosis combinatorial therapy. This innovation effectively addresses key challenges in BBB traversal and tumor-specific delivery, establishing an integrated paradigm that combines molecular design, biomimetic engineering, and multimodal therapeutic synergy for advanced GBM theranostics.