Abstract

Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood–brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.