Iron oxide/lipid nanoparticles loaded with traditional Chinese medicine CGXJF constituents inhibit pancreatic cancer progression

Abstract Pancreatic cancer is a disease with strong invasiveness, poor prognosis, and little possibility of survival. This is mainly due to the dense structure formed by fibroblasts, which limits the drug dosage of chemotherapy scheme, making the treatment scheme of most pancreatic cancer patients more toxic. With the exploration of the application of nanomedicine and traditional Chinese medicine in cancer treatment, the combination of the two is expected to become an advanced adjuvant therapy for cancer in the future. Hence, we propose a novel biologics–herbal integration strategy based on nanostructural engineering to enhance the targeting ability of traditional Chinese medicine while preserving the systemic regulatory advantages of traditional formulations. Ginsenoside rb1 (GRB1) isolated from Chai‐gui‐xiao‐ji formula (CGXJF, a tonifying Yuan qi and detoxification herbal complex) revealed unexpected dual activity: immunostimulatory effects via myeloid cell activation and neuromodulatory suppression of cancer‐associated neural remodeling, while mitigating neuropathic sequelae. Given the unique pathophysiological constraints of pancreatic tumor microenvironment (TME) and inherent bioavailability limitations of phytotherapeutic agents, we engineered and characterized LIP/Fe 3 O 4 ‐PEP‐GRB1 NPs‐subunit nanostructures capable of penetrating the fibrotic stromal barrier while achieving tumoral drug enrichment. Mechanistic validation confirmed that these nanoarchitectures serve as pharmacodynamic determinants that potentiate CGXJF's therapeutic bioactivity. Compared to native GRB1, LIP/Fe 3 O 4 ‐PEP‐GRB1 NPs demonstrated superior potency in suppressing pancreatic cancer proliferation and invasion across in vitro and in vivo paradigms. These findings present LIP/Fe 3 O 4 ‐PEP‐GRB1 NPs as multimodal therapeutic candidates that simultaneously address TME penetration challenges and malignant reprogramming inhibition.