Stealthy systemic circulation of spatially controlled tumor microenvironment-activated bioadhesive proteinic nanoparticles for pancreatic cancer chemotherapy.

Pancreatic cancer remains one of the deadliest malignancies, largely due to late diagnosis and the limited efficacy of systemic chemotherapy. Here, we propose a tumor microenvironment-activated bioadhesive nanoparticle platform designed to enhance intratumoral drug retention and therapeutic efficacy following systemic intravenous administration. The system was based on bioengineered mussel adhesive protein (MAP)-derived nanoparticles that were conjugated with polyethylene glycol (PEG) shielding linked via a matrix metalloproteinase-2 (MMP2)-cleavable peptide, enabling stealth systemic circulation and tumor-specific deshielding. Upon exposure to the MMP2-rich tumor microenvironment, the PEG layer was selectively removed, restoring strong wet tissue adhesion and promoting sustained intratumoral release of anticancer drugs. Gemcitabine-loaded shielded MAP nanoparticles (Gem-S-MNPs) demonstrated efficient drug encapsulation and enzyme-mediated PEG deshielding, which restored MAP adhesiveness and consequently enhanced anticancer efficacy against pancreatic cancer cells compared with free gemcitabine. In vivo evaluation through intravenous systemic administration of Gem-S-MNPs demonstrated superior intratumoral accumulation and prolonged retention of gemcitabine-loaded deshielded MAP nanoparticles (Gem-dS-MNPs), resulting in effective tumor growth suppression without observable systemic toxicity. Histological analyses further confirmed extensive apoptosis and necrosis within tumor tissues following treatment. Collectively, the proposed systemic administrable spatially controlled tumor microenvironment-activated bioadhesive nanoparticle platform offers a promising approach to address key limitations of conventional systemic chemotherapy for pancreatic cancer.