Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to excessive hyaluronic acid (HA) accumulation, which impedes drug delivery. Here, we present a targeted approach to reduce HA production by specifically silencing glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), a key enzyme of the hexosamine biosynthesis pathway (HBP) in pancreatic cancer cells. An engineered liposomal system for siGFAT1 delivery, PMLip@siGFAT1, characterized by macrophage membrane camouflage, LFC131 peptide-mediated targeting, and calcium phosphate (CaP) as the core, was designed to ensure prolonged circulation, enhanced inflamed vascular endothelial penetration, and subsequent effective tumor cell uptake and endosomal escape. Consequently, PMLip@siGFAT1 markedly downregulated the HA level in the PDAC microenvironment, decompressing the tumor vasculature and weakening the stromal barrier, which in turn improved the permeability of chemotherapeutics. In combination with Doxil, PMLip@siGFAT1 demonstrated potent antitumor efficacy with minimal systemic toxicity. Importantly, unlike PEGPH20 (hyaluronidase), PMLip@siGFAT1 reduced tumor invasiveness, while preserving skeletal muscle integrity. These findings highlight that PMLip@siGFAT1 holds great potential to revitalize HA downregulation strategies in pancreatic cancer for enhanced drug delivery and efficacy.