Parallelism to Conquer: Binary Supramolecular Peptide Amphiphiles Launch Synergistic Stromal Reprogramming to Remove the Baffle in Pancreatic Cancer Therapy

In pancreatic cancer, the activation of quiescent pancreatic stellate cells (PSCs) is a critical event that leads to a characteristic dense desmoplastic stroma. The fibrotic network resulting from the bidirectional cross talk between pancreatic cancer cells (PCCs) and PSCs creates a complex tumor microenvironment that considerably hinders drug delivery and penetration. To improve pancreatic cancer treatment, a promising parallelization strategy with cross-action property is urgently required that can simultaneously act on PCCs and PSCs to normalize activated PSCs (aPSCs), that is reverse them back to quiescent phenotype. Herein, a novel parallelization delivery system (CoA-A & B-gamma PGA) with dual-pathway PSC quiescence restoration functions is designed. Metformin downregulates the secretion of transforming growth factor-beta in PCCs, and all-trans-retinoic acid re-educates aPSCs. CoA-A & B-gamma PGA thus induces aPSC quiescence and homeostatic restoration of desmoplastic stroma in vitro and in vivo. Importantly, CoA-A & B-gamma PGA exhibits deep penetration, improved accumulation and long-term retention, and enhanced combination chemotherapy effects in multicellular spheroid and xenograft models. Furthermore, this dual-targeting and co-delivery system shows high specificity and sensitivity for detecting pancreatic cancer in patient samples. The innovative but simple peptide amphiphile co-assembly strategy provides a new paradigm to design desired nanomedicines for stroma-enriched pancreatic cancer therapy.