Overcoming stromal barriers in pancreatic cancer via size-engineered carrier-free nano-prodrugs

Abstract

Pancreatic cancer remains a major therapeutic challenge due to its dense desmoplastic stroma, which limits drug penetration and reduces chemotherapy efficacy. Here, we report a carrier-free nanoprodrug (CFNPG) based on SNC4DC, a homodimeric prodrug of SN-38, enabling controlled SN-38 release in pancreatic cancer cells. Using a precisely controlled reprecipitation method, we generated stable CFNPGs with tunable particle sizes down to ∼30 nm, resulting in enhanced tissue penetration. These nanoparticles exhibited high drug loading, absence of carrier-associated toxicity, potent antitumor activity, and minimal systemic side effects in an orthotopic pancreatic cancer model, providing a physiologically relevant assessment of drug delivery. Our findings demonstrate that precise size engineering of carrier-free nanoprodrugs can significantly improve tissue penetration and therapeutic efficacy, providing a clinically translatable strategy for pancreatic cancer therapy.