Strengthening Antisense Oligonucleotide-Mediated Anti-Tumor Immunity via Metal-Organic Framework Nanoparticles.

Abstract

Tumor overexpression of programmed death-ligand one (PD-L1) inhibits immune recognition. Existing monoclonal antibodies are fragile and penetrate tumors poorly, leading to variable outcomes. Antisense oligonucleotides (ASOs) can reduce PD-L1 expression, but require frequent high dosing due to rapid degradation, clearance, and poor uptake. To overcome this, we harnessed metal-organic frameworks (MOFs) to protect and deliver ASOs, reducing PD-L1 expression and elevating downstream immunity. With various PD-L1-specific ASOs loaded into NU-1000 MOFs, we sustain release up to 7 days, reduce PD-L1 expression across triple negative breast cancer and melanoma, and stimulate dendritic cells to amplify T cell proliferation. This dual tumor and immune cell modulation via MOF-mediated ASO delivery increases tumor caspase-3 expression and killing of human melanoma with patient tumor-infiltrating lymphocytes, and elongates <i>in vivo</i> survival. This research highlights a strategy to utilize ASOs without sequence modifications and with a reduced dosing frequency, enabling broadly applicable oncogene-targeting oligonucleotide delivery.