The inability to cross the blood−brain barrier (BBB) prevents nearly all chemotherapeutics and biotherapeutics from the effective treatment of brain tumors, rendering few improvements in patient survival rates to date. Here, we report that apolipoprotein E peptide [ApoE, (LRKLRKRLL) 2 C] specifically binds to low-density lipoprotein receptor members (LDLRs) and mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted protein therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared to Angiopep-2, the best-known BBB-crossing peptide used in clinical trials for GBM therapy. ApoE-installed CP (ApoE−CP) carrying saporin (SAP) displays a highly specific and potent antitumor effect toward U-87 MG cells with a low half-maximum inhibitory concentration of 14.2 nM SAP. Notably, ApoE−CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE−CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM therapy.

Glioblastoma is a most intractable and high-mortality malignancy because of its extremely low drug accessibility resulting from the blood-brain barrier (BBB). Here, it is reported that angiopep-2-directed and redox-responsive virus-mimicking polymersomes (ANG-PS) (angiopep-2 is a peptide targeting to low-density lipoprotein receptor-related protein-1 (LRP-1)) can efficiently and selectively chaperone saporin (SAP), a highly potent natural protein toxin, to orthotopic human glioblastoma xenografts in nude mice. Unlike chemotherapeutics, free SAP has a low cytotoxicity. SAP-loaded ANG-PS displays, however, a striking antitumor activity (half-maximal inhibitory concentration, IC = 30.2 × 10 m) toward U-87 MG human glioblastoma cells in vitro as well as high BBB transcytosis and glioblastoma accumulation in vivo. The systemic administration of SAP-loaded ANG-PS to U-87 MG orthotopic human-glioblastoma-bearing mice brings about little side effects, effective tumor inhibition, and significantly improved survival rate. The protein toxins chaperoned by LRP-1-targeted virus-mimicking vesicles emerge as a novel and highly promising treatment modality for glioblastoma.

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The clinical translation of protein drugs that act intracellularly is limited by the absence of safe and efficient intracellular protein delivery vehicles. Here, pH-sensitive coiled-coil peptide-cross-linked hyaluronic acid nanogels (HA-cNGs) were designed and investigated for targeted intracellular protein delivery to CD44 overexpressing MCF-7 breast cancer cells. HA-cNGs were obtained with a small size of 176 nm from an equivalent mixture of hyaluronic acid conjugates with GY(EIAALEK)GC (E3) and GY(KIAALKE)GC (K3) peptides, respectively, at pH 7.4 by nanoprecipitation. Circular dichroism (CD) proved the formation of coiled-coil structures between E3 and K3 peptides at pH 7.4 while fast uncoiling at pH 5.0. HA-cNGs showed facile loading of cytochrome C (CC) and greatly accelerated CC release under mild acidic conditions (18.4%, 76.8%, and 91.4% protein release in 24 h at pH 7.4, 6.0, and 5.0, respectively). Confocal microscopy and flow cytometry displayed efficient internalization of CC-loaded HA-cNGs and effective endosomal escape of CC in MCF-7 cancer cells. Remarkably, HA-cNGs loaded with saporin, a ribosome inactivating protein, exhibited significantly enhanced apoptotic activity to MCF-7 cells with a low IC of 12.2 nM. These coiled-coil peptide-cross-linked hyaluronic acid nanogels have appeared as a simple and multifunctional platform for efficient intracellular protein delivery.

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