Self-Crosslinked Albumin Nanoparticles for Targeted Doxorubicin Delivery in Glioblastoma

We engineered a protein-based nanoplatform exploiting the intrinsic disulfide network of human serum albumin (HSA) to generate self-crosslinked, redox-responsive nanoparticles without synthetic crosslinking agents. Following folic acid conjugation, HSA nanoparticles (f-HNPs) were prepared by desolvation-assisted self-crosslinking and loaded with doxorubicin (DOX) with 88% encapsulation efficiency. The resulting nanoparticles were spherical, with an average diameter of 37 ± 5 nm and PDI of 0.24, and underwent glutathione-triggered destabilization and accelerated drug release under reducing conditions. Empty f-HNPs showed excellent biocompatibility, whereas DOX@f-HNPs enhanced DOX cytotoxicity against U-87MG glioblastoma cells, reducing the IC50 from 0.24 to 0.17 μg mL−1. Competitive inhibition experiments supported folate receptor-mediated uptake and enhanced intracellular drug accumulation. Nanoparticle-mediated delivery increased oxidative stress, mitochondrial depolarization, and G2/M cell-cycle arrest, accompanied by p21 upregulation, Cyclin D1 and Ki67 downregulation, and sustained inhibition of glioblastoma cell proliferation.