3‑IndoleaceticAcid-Modified Chondroitin Sulfate-MediatedPaclitaxel Nanocrystal Assembly for the Treatment of Pancreatic Cancer

High drug-loading nanocrystals show significant advantages in delivering hydrophobic small-molecule drugs. However, these nanocrystals face challenges, including inherent instability and limited targetability. In this study, we developed a paclitaxel nanocrystal delivery platform based on chondroitin sulfate modified with 3-indoleacetic acid (CS-IAA). Paclitaxel and CS-IAA assembled into stable nanocrystals (PTX@CS-IAA, PC) with a high drug loading (up to 46.6%), facilitated by π–π stacking and hydrophobic interactions. CS-IAA targets tumors through CD44 receptors, which helps to minimize off-target effects. Additionally, CS-IAA, serving as a functional delivery vehicle, can significantly increase reactive oxygen species (ROS) levels at the tumor site. In an orthotopic pancreatic cancer mouse model, PTX@CS-IAA nanocrystals showed significantly enhanced antitumor effects. When PTX@CS-IAA was combined with the αPD-L1 antibody, the survival of mice with pancreatic tumors was further prolonged. This study provides valuable insights into alternative treatment options for pancreatic cancer, with the potential to improve patient prognosis and survival.