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

Abstract 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‐γPGA) 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‐γPGA thus induces aPSC quiescence and homeostatic restoration of desmoplastic stroma in vitro and in vivo. Importantly, CoA‐A&B‐γPGA 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.