Nanotechnology-based PD-L1 siRNA codelivery systems for improving cancer immunotherapy.

Immune checkpoint blockade targeting the PD-1/PD-L1 (Programmed cell death protein 1/Programmed death-ligand 1) axis has transformed cancer therapy. However, antibodies non-specifically bind to PD-1 or PD-L1 on both malignant and normal cells, resulting in immune-related adverse events and limited therapeutic selectivity. Additionally, antibodies only target cell-surface PD-1/PD-L1, whereas intracellular proteins can translocate to the membrane, enabling immune evasion. In contrast, small interfering RNA (siRNA) can specifically silence PD-1 or PD-L1 on the cell surface and within the cytoplasm, mitigating immune suppression, reducing drug resistance, and limiting systemic off-target effects. Despite the clinical success of immune checkpoint inhibitors, monotherapy benefits only a fraction of patients. Combination therapies incorporating chemotherapy, radiotherapy, or photo-mediated therapy have shown improved efficacy. Nanoparticles offer a promising approach for combination therapy by overcoming RNA delivery challenges, enabling efficient tumour-targeting capacity, providing tumour-responsive behaviour, and versatility for combination therapy. This review presents an overview of different nanoparticles, including polymer and lipid nanoparticles, developed for the codelivery of PD-L1 siRNA and other therapeutic modalities with different properties. Furthermore, discusses mechanisms underlying PD-L1-mediated tumour therapy, and finally, highlights current challenges and perspectives for translating nanoparticle-based combinatorial immunotherapy into clinical applications.