Dual-Site Förster Resonance Energy Transfer Route of Upconversion Nanoparticles-Based Brain-Targeted Nanotheranostic Boosts the Near-Infrared Phototherapy of Glioma

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with low survival, primarily due to the blood-brain barrier (BBB) and high infiltration. Upconversion nanoparticles (UCNPs)-based near-infrared (NIR) phototherapy with deep penetration is a promising therapy method against glioma but faces low photoenergy utilization that is induced by spectral mismatch and single-site Förster resonance energy transfer (FRET). Herein, we designed a brain-targeting NIR theranostic system with a dual-site FRET route and superior spectral matching to maximize energy utilization for synergistic photodynamic and photothermal therapy of glioma. The system was fabricated by Tm-doped UCNPs, zinc tetraphenylporphyrin (ZnTPP), and copper sulfide (CuS) nanoparticles under multioptimized modulation. First, the Tm-doping ratio was precisely adjusted to improve the relative emission intensity at 475 nm of UCNPs (11.5-fold). Moreover, the J-aggregate of ZnTPP increased the absorption at 475 nm (163.5-fold) of monomer; both together optimize the FRET matching between UCNPs and porphyrin for effective NIR photodynamic therapy. Simultaneously, the emission at 800 nm was utilized to magnify the photothermal effect of CuS nanoparticles for photothermal therapy via the second FRET route. After being modified by a brain-targeted peptide, the system efficiently triggers the synergistic phototherapy ablation of glioma cells and significantly prolongs the survival of orthotopic glioma-bearing mice after traversing the BBB and targeting glioma. This success of advanced spectral modulation and dual-site FRET strategy may inspire more strategies to maximize the photoenergy utilization of UCNPs for brain diseases.