The dense stromal barrier of pancreatic tumors significantly hinders the delivery of therapeutic drugs, posing a major challenge for effective gene therapy of pancreatic cancer. This article presents a strategy that utilizes the extracellular matrix component hyaluronic acid (HA) of pancreatic tumor cells to encapsulate dual-enzyme-responsive DNA nanoflowers into intelligent nanocarriers, which can respond to multiple tumor-related endogenous nucleases, aiming to co-deliver Cas9/sgRNA ribonucleoproteins (RNPs) and antisense oligonucleotides (ASOs) to deep pancreatic tumors. This enables efficient and synergistic gene therapy for pancreatic cancer. These DNA nanoflowers are assembled from extremely long single-stranded DNA and have multiple sgRNA recognition sequences, enabling efficient loading and delivery of Cas9/sgRNA RNPs and ASOs. The HA coating significantly enhances the penetration ability of the DNA nanoflowers in pancreatic tumors by approximately 5 times and increases by approximately 15.8 times in cancer cells. In pancreatic cancer cells, the overexpressed ribonuclease H and flap structure-specific endonuclease 1 respectively trigger the release of Cas9/sgRNA RNPs and ASOs, thereby promoting precise and effective gene editing and silencing. In the pancreatic cancer mouse model studies conducted in vivo, the significant therapeutic effect was remarkable, with a tumor inhibition rate of approximately 91.9%, highlighting the potential of high-level cell protein DNA nanoflowers as a treatment strategy for pancreatic cancer. This study was published in Advanced Functional Materials under the title "Hyaluronic Acid-Coated DNA Nanoflowers as Smart Nanocarriers for Deep Tumor Penetration and Enhanced Gene Therapy in Pancreatic Cancer".
References: DOI: 10.1002/adfm.202531547