Integrating gene demethylation and immune modulation: PD-1 nanovesicles as a dual-action therapy for NSCLC

Non-small cell lung cancer (NSCLC) remains a formidable challenge in oncology, underscoring the urgent need for innovative therapeutic strategies. This study explores the potential of PD-1-modified multifunctional nanovesicles (NVs) loaded with 5-azacytidine (5-Aza) for NSCLC treatment. By integrating bioinformatics analyses with <i>in vitro</i> and <i>in vivo</i> experiments, methylation-driven genes closely associated with NSCLC progression and prognosis-CLEC3B, CYP27A1, CYP4B1, and NR0B2-were identified. Functional assays revealed that 5-Aza effectively demethylates these genes, reducing NSCLC cell proliferation, migration, and invasion. PD-1-modified NVs demonstrated precise targeting of NSCLC cells via PD-L1 binding, while the combination of PD-1 NVs and 5-Aza synergistically enhanced peripheral blood mononuclear cell activation, induced apoptosis, and amplified anti-tumor immunity. <i>In vivo,</i> studies confirmed the tumor-targeting ability and significant therapeutic efficacy of PD-1 NVs. This synergistic strategy of epigenetic modulation and immune activation offers a promising avenue for NSCLC management. These findings contribute valuable insights into developing targeted nanotherapeutics for effective NSCLC treatment.