Enhanced Precision Immunotherapy of Colorectal Cancer through Chemo‐Photothermal Nanoparticles via Endoplasmic Reticulum Stress Mediated Apoptotic Pathways

Abstract Colorectal cancer (CRC) stands out as one of the most prevalent gastrointestinal cancers. Current treatment strategies for CRC are significantly hindered by systemic toxicity and suboptimal therapeutic efficacy. This study aims to overcome these limitations by developing a robust tumor‐targeting chemo‐photothermal strategy, combining Bortezomib (BTZ) as a proteasome inhibitor, IR780 iodide as a near‐infrared dye, and Photothermal Therapy (PTT) agent, with hyaluronic acid (HA) serving as the shell for tumor targeting, denoted as HA/PB@IR780. The investigations reveal the impressive tumor‐targeting affinity of HA/PB@IR780, leading to a synergistic chemo‐photothermal therapeutic effect both in vitro and in vivo. Additionally, this material demonstrates the capability for drug release triggered by low pH conditions. Moreover, HA/PB@IR780 induced the generation of reactive oxygen species (ROS), triggered cells apoptosis via the PERK‐CHOP‐Bcl‐2 pathway, and induced Immunogenic Cell Death (ICD) in CT26 cells. Importantly, HA/PB@IR780 selectively targets tumor sites, mitigating systemic toxic side effects and significantly extending the survival of CT26 tumor‐bearing mice. In conclusion, this designed tumor‐targeting nanocarrier represents a promising and potentially effective platform for the precise treatment of CRC.