Losartan primes pancreatic tumors for effective exosome-biomimetic chemo-immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is protected by a dense fibrotic stroma that restricts drug delivery and enforces immune exclusion. We describe a clinically actionable, two-stage strategy in which losartan preconditioning transiently converts a high-stiffness tumor microenvironment into a more compliant state with reduced mechanical resistance and thereby enables efficient delivery of an exosome-liposome hybrid nanoparticle (IGEL) co-encapsulating gemcitabine and IL-12 circular RNA. In orthotopic, stroma-rich PDAC models, losartan pretreatment increased vascular perfusion and nanoparticle penetration, reprogrammed the tumor microenvironment toward immune activation, suppressed tumor growth, prolonged survival, and reduced systemic gemcitabine toxicity. Multimodal imaging demonstrated improved perfusion and deeper intratumoral accumulation of IGEL after losartan, while transcriptomic profiling indicated coordinated remodeling of the stromal compartment and the tumor immune microenvironment. These results indicate that transient stromal normalization followed by targeted chemo-immunotherapy can overcome the dual physical and immunologic barriers of fibrotic tumors and support further translational evaluation of losartan-primed IGEL as a practical therapeutic approach for PDAC.