Smart hypoxia-responsive transformable and charge-reversible nanoparticles for the deep penetration and tumor microenvironment modulation of pancreatic cancer

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL)(n)@Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart code -livery strategy provides an inspiring opportunity in PDAC treatment.

Automated summary

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) hinders drug delivery and breaking the barrier can lead to uncontrollable growth and metastasis. Researchers have developed a smart nanoparticle that can reduce in size in the tumor microenvironment, promote drug penetration, and inhibit overactivated STAT3, changing the tumor microenvironment into an immune-activated state. This provides an inspiring opportunity in PDAC treatment.