uPAR-targeted stealth small-sized mesoporous silica nanoparticles for pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma and aberrant tumor-associated vasculature, which impede nanoparticle (NP) penetration and accumulation, thereby reducing therapeutic efficacy. To overcome these barriers, small, selective NPs with prolonged circulation times are essential for effective tumor tissue penetration. In this study, mesoporous silica nanoparticles (MSNs) with a diameter of 45 nm were synthesized and coated with an albumin corona using a novel pH-sensitive "click" acetal linker. The albumin corona acts as a pH-responsive gatekeeper and scaffold, decorated with two distinct peptides: U11 and a CD47-derived "minimal peptide." The U11 peptide enables active targeting of PDAC cells, increasing NP uptake by 1.6- and 2.2-fold in MIA PaCa-2 and PANC-1 cells, respectively. The CD47-mimicry peptide promotes immune evasion, reducing macrophage uptake in RAW 264.7 cells by 2.3-fold compared to uncoated MSNs. The NPs were loaded with a camptothecin (CPT) gemcitabine (GEM) conjugate. The cytotoxicity of this pH-sensitive nanocarrier was evaluated in vitro against PANC-1 and MIA PaCa-2 pancreatic cancer cell lines.