Sequential Dual Nanoparticle Approach for Extracellular Matrix Remodeling and Targeted Chemotherapy through Liposome–Exosome Hybridization in Pancreatic Cancer

Pancreatic cancer remains one of the most aggressive and treatment-resistant malignancies, with a poor prognosis and limited response to conventional therapies. Although liposomal doxorubicin (DOX) formulations reduce systemic toxicity, their clinical use is constrained by insufficient tumor targeting and poor intratumoral penetration. Here, we report a sequential dual-nanoparticle approach that integrates extracellular matrix (ECM) remodeling with tumor-targeted chemotherapy to overcome these barriers. Hyaluronidase-loaded liposomes (LH) were first employed to degrade hyaluronic acid-rich ECM, followed by the administration of DOX-loaded liposome-exosome hybrid nanoparticles (HLD) engineered using pancreatic cancer cell-derived exosomes to confer intrinsic tumor-homing capability. The DOX-loaded hybrid nanoparticles demonstrated enhanced cellular uptake, potent cytotoxicity, and strong immunogenic cell death (ICD) responses in pancreatic cancer cells. ECM degradation by LH significantly improved intratumoral accumulation and penetration of subsequently administered HLD in vivo. In a pancreatic cancer xenograft model, sequential LH and HLD treatment resulted in superior tumor growth suppression compared with monotherapies, without inducing systemic toxicity. Collectively, this work demonstrates a modular, sequential nanotherapeutic platform that synergistically combines ECM remodeling and exosome-mediated targeting, offering a promising strategy to improve drug delivery and therapeutic efficacy in stromal-dense solid tumors, such as pancreatic cancer.