Engineering ApoE-Mimetic HDL-Like Nanoparticles for Glioblastoma-Targeted Theranostics

Glioblastoma theranostics remain limited by the tumor's blood-brain-barrier (BBB), infiltrative growth, and heterogenous, treatment-resistant cell populations. Here, we engineered self-assembled high-density lipoprotein (HDL)-like nanoparticles functionalized with an apolipoprotein E-mimetic peptide (ApoEm), designed to recapitulate and strengthen the multireceptor-mediated transport properties of native apolipoprotein E3 (ApoE3). Competition and receptor inhibition studies demonstrate coordinated uptake of ApoEm-HDL nanoparticle via low-density lipoprotein receptor, low-density lipoprotein receptor-related protein 1, and scavenger receptor class-B type 1, which are expressed at BBB and upregulated in glioblastoma. Incorporation of porphyrin-lipid into the HDL-like scaffold yielded ApoEm porphyrin-lipoprotein nanoparticles (ApoEm-PLP) with a uniform, spherical morphology (∼30 nm). ApoEm-PLP increased porphyrin uptake relative to ApoE3-PLP across multiple glioblastoma cell lines (∼seven-fold in U87 cells, ∼four-fold in T98, and GL261-Luc cells) and induced ∼two-fold greater photodynamic therapy (PDT) efficacy in U87 cells. In an orthotopic U87 glioblastoma model, intravenous administration of ApoEm-PLP achieved ∼13-fold higher tumor porphyrin accumulation than normal brain, with homogeneous intratumoral distribution and pronounced peri-tumoral deposition. Transcranial PDT using ApoEm-PLP elicited widespread tumor damage. These findings establish ApoEm-HDL-like nanoparticles as a promising theranostic platform for uniform glioblastoma porphyrin delivery and effective phototherapy, with potential to address the infiltrative and heterogenous nature of glioblastoma.