Apolipoprotein E Peptide-Directed Chimeric Polymersomes Mediate an Ultrahigh-Efficiency Targeted Protein Therapy for Glioblastoma

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)2C] 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.