Engineered Exosomes Disguised NIR-II Nanoaggregates for High-Resolution Photoacoustic Angiography and Robust Photothermal Therapy of Glioblastoma

Glioblastoma (GBM) ranks as the most malignant tumor of the central nervous system. The blood-brain barrier (BBB) poses a formidable obstacle to drug delivery, while traditional invasive therapeutic modalities are plagued by substantial side effects and dismal prognosis. In this study, we engineered exosome-encapsulated near-infrared II (NIR-II) nanoaggregates (LY@R-Exo) for photothermal therapy of GBM under 1319 nm laser excitation. The meticulously synthesized dye LY exhibited the capacity to spontaneously self-assemble into nanoaggregates even within the tumor microenvironment, with its absorption peak undergoing a significant bathochromic shift to the 1300-1400 nm range. Density functional theory (DFT) calculations elucidated that LY molecules formed nanoaggregates via hydrogen bonding, π-π stacking, and CH-π interactions. LY@R-Exo demonstrated exceptional photothermal conversion efficiency (PCE), reaching up to 53.6%, and selectively targeted mitochondria and triggered apoptosis in U87 MG cells by disrupting mitochondrial membrane potential upon laser irradiation. In addition, LY@R-Exo could clearly visualize tumor vascular heterogeneity via NIR-II photoacoustic imaging, achieving a resolution of 0.12 mm and a maximum signal-to-background ratio (SBR) of 14.2. Mediated by RVG29-modified exosomes, LY@R-Exo efficiently penetrated the BBB and accumulated precisely at GBM sites, reducing tumor volume after photothermal therapy without biosafety issues. Intravenously administered LY@R-Exo achieved therapeutic efficacy comparable to that of stereotactic intracerebral injected LY, while offering the distinct advantage of noninvasiveness. Therefore, LY@R-Exo pioneers a novel paradigm for GBM therapy.