Transcytosis-Triggering Nanoparticles for Overcoming Stromal Barriers and Reversing Immunosuppression in Pancreatic Cancer Combinatorial Therapy

In pancreatic ductal adenocarcinoma (PDAC), stromal cells and matrix proteins form a dense physical barrier that, while preventing the outward spread of tumor cells, also limits the penetration of drugs and CD8⁺ T cells inward. Additionally, the overactivated TGF-β/SMAD signaling pathway further promotes matrix proliferation and immune suppression. Therefore, crossing the stromal barrier while preserving the integrity of the stroma, releasing drugs intratumorally, remodeling the stroma, and activating the immune system is a promising drug delivery strategy. In this work, a type of enamine <i>N</i>-oxides modified nanoparticle was prepared, with stearic acid-modified gemcitabine prodrug (GemC18) and <i>p</i>SMAD2/3 inhibitor galunisertib encapsulated. The peripheral enamine <i>N</i>-oxides can trigger transcytosis and then respond to hypoxia and acidic microenvironments, turning the surface charge of the nanoparticles to a positive charge and enhancing penetration. The released galunisertib inhibits the TGF-β/SMAD signaling pathway, reshapes the matrix, activates antitumor immunity, and combines with gemcitabine (Gem) to kill tumor cells.