T7 peptide-modified erythrocyte membrane-camouflaged amphiphilic self-delivery biomimetic nanodrug for targeting therapy oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a common oral malignancy. However, conventional chemotherapeutic strategies present many limitations. To overcome these challenges, a cell membrane-camouflaged amphiphilic self-delivery nano-prodrug was developed for the targeted treatment of OSCC. In this system, the hydrophobic anticancer drug methotrexate (MTX) and the hydrophilic drug gemcitabine (GEM) were conjugated <i>via</i> amide bonds to form an amphiphilic drug-drug conjugate (ADDC), which self-assembled into nanoparticles (MG NPs). Phospholipids were modified with T7 peptide, capable of targeting the highly expressed transferrin receptor (TFR) on tumor cell surfaces, and subsequently loaded onto red blood cell membranes (RBCM) to prepare T7 peptide-modified RBCM (T7-RBCM). The MG NPs were then encapsulated with T7-RBCM by co-extrusion to form T7-RBCM@MG NPs. <i>In vitro</i> studies demonstrated that T7-RBCM@MG NPs were more efficiently internalized by tumor cells due to specific recognition between the T7 peptide and TFR, exhibited stronger inhibitory activity against SCC-7 cells, and significantly induced apoptosis. <i>In vivo</i> experiments confirmed that T7-RBCM@MG NPs exhibited favourable biosafety, prolonged circulation, and enhanced tumor-targeting delivery, resulting in significant tumor growth inhibition without notable toxicity to major organs.