Unleashing a Dual‐Warhead Nanomedicine to Precisely Sensitize Immunotherapy for Pancreatic Ductal Adenocarcinoma

Abstract Despite remarkable achievements in cancer immunotherapy, significant challenges persist in pancreatic ductal adenocarcinoma (PDAC) treatment. Particularly, there is a critical issue of inadequate intratumoral infiltration of effector T cells, primarily attributed to the physical “hard” barrier caused by extracellular matrix (ECM) and the “soft” barrier imposed by immune suppression. Here, a dual‐warhead nanomedicine is reported that effectively targets and attacks the barriers to precisely sensitize PDAC immunotherapy. The nanomedicine is achieved by designing tumor cell membrane vesicle (TMV)‐coated polyamidoamine dendrimer‐condensed siRNA complexes, with hedgehog inhibitor encapsulated in TMV bilayers. With the precision‐guided stealth feature of TMV coating, the nanomedicine achieved powerful tumor‐targeting co‐delivery of hedgehog inhibitor and siRNA, resulting in a significant decrease in collagen I secretion and efficient silencing of the target gene to disrupt the ECM and immune suppression barriers. This nanomedicine enables robust immunity against PDAC progression and metastasis, offering a potent approach to PDAC therapy.