Transferrin receptor (TFR) is highly expressed on both the blood-brain barrier (BBB) and glioblastoma (GBM) cells, making it an attractive target for therapeutic intervention. Based on this rationale, we designed a Transferrin-engineered NK cells (TF-NK) using a multifunctional polymeric biomaterial for NK cell surface engineering consisting of (1) TF, a TFR ligand; (2) PEG, a penetration blocker; and (3) lipid moieties, cell membrane anchor via hydrophobic interactions. Due to the structural complexity of TF, a TF-binding peptide (TBP) was introduced as a molecular intermediary to enable stable membrane immobilization of TF. The specific and strong binding interaction between TF and TBP was investigated by molecular dynamics simulations and validated using BLI and cell capture assays under dynamic flow conditions. As a result, tumor eradication was achieved in 75% of treated mice following TF-NK cell therapy, driven by enhanced TFR-mediated recognition at the BBB and GBM sites.