Glioblastoma multiforme (GBM) remains therapeutically challenging due to the blood–brain barrier (BBB) and intrinsic tumor heterogeneity, significantly reducing drug efficacy. This study describes the engineering of multifunctional poly-DL-lactic-co-glycolic acid nanoparticles (PNP) loaded with temozolomide (TMZ) and surface-modified with polyamidoamine dendrimer (PD) and hyaluronic acid (HA), specifically designed for enhanced BBB penetration, receptor-mediated tumor targeting, and sustained drug release. PNP–TMZ@HA–PD were prepared via optimized nanoprecipitation using Vitamin E as a stabilizer, with PD and HA conjugation achieved through 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide chemistry. Characterization revealed optimal physicochemical parameters (particle size: ∼100 nm; polydispersity index: <0.15; and zeta potential: ≈ −20 mV), high drug encapsulation efficiency (91.66 %), and TMZ amorphization. Functionalized nanoparticles exhibited pH-sensitive release profiles (∼95.5 % at pH 5.5), robust stability in physiological environments, and minimal serum protein-induced aggregation. In vitro studies using U-87 MG cells confirmed significantly enhanced cellular uptake via HA-mediated CD44 receptor targeting, resulting in marked improvements in cytotoxicity (IC50 = 4.98 μg/mL), reactive oxygen species (ROS) generation, and apoptotic induction compared to free TMZ. Thus, PNP–TMZ@HA–PD demonstrates significant therapeutic potential as a targeted nanotherapeutic platform for GBM, meriting further in vivo evaluation toward clinical translation.