Sirna-Mediated Mismatch Repair Disruption Synergizes with Oxaliplatin to Restore Immune Surveillance in Microsatellite-Stable Colorectal Cancer

Proficient mismatch repair/microsatellite-stable colorectal cancer (pMMR/MSS CRC), which represents the majority of clinical cases, exhibits low tumor mutational burden and minimal responsiveness to immune checkpoint blockade. Disrupting the MMR system has been shown to resensitize pMMR/MSS CRC to immune surveillance; however, direct MMR inhibitors are currently unavailable. Here, we bridge this gap by developing small interfering RNA lipid nanoparticles (siMMR@LNPs) capable of silencing key MMR genes, including MLH1, MSH2, and MSH6, achieving over 70