Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults. Hidden behind the blood-brain and blood-tumor barriers (BBTB), this invasive type of brain tumor is not readily accessible to nano-sized particles. Here we demonstrate that fluorescent indocarbocyanine lipids (ICLs: DiD, DiI) formulated in PEGylated lipid nanoparticle (PLN) exhibit highly efficient penetration and accumulation in GBM. PLN-formulated ICLs demonstrated more efficient penetration in GBM spheroids and organoids in vitro than liposomal ICLs. Over 82% of the tumor's extravascular area was positive for ICL fluorescence in the PLN group versus 13% in the liposomal group just one hour post-systemic injection in the intracranial GBM model. Forty-eight hours post-injection, PLN-formulated ICLs accumulated in 95% of tumor myeloid-derived suppressor cells and macrophages, 70% of tumor regulatory T cells, 50% of tumor-associated microglia, and 65% of non-immune cells. PLN-formulated ICLs extravasated better than PEGylated liposomal doxorubicin and fluorescent dextran and efficiently accumulated in invasive tumor margins and brain-invading cells. While liposomes were stable in serum in vitro and in vivo, PLNs disassembled before entering tumors, which could explain the differences in their extravasation efficiency. These findings offer an opportunity to improve therapeutic cargo delivery to invasive GBM.

胶质母细胞瘤（GBM）是成人中最具破坏性和侵袭性的脑肿瘤。这种侵袭性脑肿瘤隐藏在血脑屏障和血肿瘤屏障（BBTB）后面，纳米尺寸的颗粒不易接近。在这里，我们证明了以聚乙二醇化脂质纳米颗粒（PLN）配制的荧光吲哚羰花青脂质（ICL：DiD、DiI）在 GBM 中表现出高效的渗透和积累。 PLN 配制的 ICL 在体外表现出比脂质体 ICL 更有效地渗透 GBM 球体和类器官。在颅内 GBM 模型中全身注射后一小时，PLN 组中超过 82% 的肿瘤血管外区域 ICL 荧光呈阳性，而脂质体组中这一比例为 13%。注射后 48 小时，PLN 配制的 ICL 在 95% 的肿瘤骨髓源性抑制细胞和巨噬细胞、70% 的肿瘤调节性 T 细胞、50% 的肿瘤相关小胶质细胞和 65% 的非免疫细胞中积累。 PLN 配制的 ICL 比聚乙二醇化脂质体阿霉素和荧光右旋糖酐更好地外渗，并在侵袭性肿瘤边缘和脑侵袭细胞中有效积累。虽然脂质体在体外和体内的血清中都很稳定，但 PLN 在进入肿瘤之前会分解，这可以解释它们外渗效率的差异。这些发现为改善侵袭性 GBM 的治疗药物输送提供了机会。