Five-in-One NIR-II phototheranostic nanomedicine for glioblastoma multiforme: Unlocking bio-barriers and photothermal-ferroptotic amplification.

Glioblastoma multiforme (GBM) remains a formidable therapeutic challenge due to its aggressive behavior, complex biological barriers, and high recurrence rates. Near-infrared II (NIR-II) phototheranostic nanomedicine has emerged as a promising strategy, offering deeper tissue penetration and enhanced photothermal effects for GBM treatment. Herein, we demonstrate an effective molecular design strategy that leverages expanded free space within aggregates to boost non-radiative decay and improve photothermal conversion efficiency (PCE). Based on this approach, we create a nanomedicine using holo-transferrin (holo-Tf) to encapsulate optimized phototheranostic agents (NDA-18). This nanosystem achieves efficient blood-brain barrier (BBB) penetration via transferrin receptor (TfR)-mediated transcytosis and selective tumor accumulation. Upon 808 nm laser irradiation, the nanomedicine enables precise photothermal therapy (PTT) while concurrently triggering ferroptosis. This ferroptosis process further enhances the PTT efficacy by suppressing heat shock proteins (HSPs), resulting in an enhanced synergistic antitumor effect. Remarkably, this one-step self-assembled nanomedicine integrates five critical functions: from BBB penetration and tumor targeting to dual-mode imaging and synergistic PTT-ferroptosis therapy. In conclusion, we have successfully developed an innovative nanoplatform that unites rational molecular design, bioengineering, and synergistic therapy for GBM treatment.