Cascade‐Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer

Abstract KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy‐immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo‐ and immunotherapy tolerance. KRAS mutation‐induced over‐expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS‐responsive positively‐charged polymer B‐PDEA is prepared and assembled into polyplexes for loading CD39‐down‐regulating small interfering RNA. Gemcitabine‐loaded albumin is coupled with the polyplexes through enzyme‐cleavable peptide, forming the intact nanoparticles for the co‐delivery of the first‐line chemotherapeutic drug and CD39‐regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic‐immune crosstalk of TME, showcasing great potential for PDAC treatment.