Novel nanoparticle-combined therapy through EGFR and PD-L1 blockade: PFPR-siRNA-mediated suppressing NSCLC proliferation via PDT and enhanced antitumor immunity.

EGFR-targeted therapy and anti-PD-1/PD-L1 immunotherapy are crucial in treating advanced or metastatic non-small cell lung cancer (NSCLC). However, therapeutic drug resistance frequently develops, leading to treatment failure. To address this, a novel nanoparticle PFPR (PDA-Fe-PEI-RGD), composed of polydopamine (PDA), iron ions, and Arg-Gly-Asp (RGD) peptides, was designed to deliver siRNA targeting EGFR and PD-L1 into NSCLC cells to investigate the nanoparticle-combined therapy to NSCLC through EGFR and PD-L1 blockade. PFPR nanoparticles can elevate ROS production in PFPR-laser-treated cultures, and significantly induce NSCLC cell death compared to control treatment. PFPR-siEGFR and PFPR-siPD-L1 markedly suppress cell proliferation, colony formation, and migration compared with PFPR-siCon, with further enhancement under laser treatment. The suppressive effects of PFPR-siRNA to NSCLC may be related to upregulation of Bax, Caspase 3, and E-cadherin, alongside downregulation of Cyclin D1 and N-cadherin. H1975 xenograft results further demonstrate significant reductions in tumor weight and volume in PFPR-siRNA-treated groups, with additional decreases upon laser irradiation. PFPR-siPD-L1 increases the proportion of CD3+CD8+ T cells and elevates CD107a and IFN-γ levels, enhancing cytotoxic activity against NSCLC. In summary, the novel PFPR nanoparticle system, synergistically combining the properties of PDA, iron, RGD, and siRNA, effectively suppresses NSCLC progression by activating photodynamic therapy (PDT) and anti-tumor immunity.