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

ABSTRACT

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.