Partial ligand shielding nanoparticles improve pancreatic ductal adenocarcinoma treatment via a multifunctional paradigm for tumor stroma reprogramming

The dense stroma that acts as a physical and biological barrier in the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) leads to the failure of chemotherapeutic drug delivery. Cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mainly constitute the refuge for cancer cells in PDAC. Herein, a CAF targeting drug delivery system (TDDS) based on RBC vesicles partial protection (RBC-Fn-NP) was established and investigated for reprogramming stroma, as well as enhancing tumor penetration and antitumor efficacy in PDAC. RBC vesicles were firstly used for partial protection of peptide from external influences. The exposed FnBPA5 peptide showed high affinity with both CAFs and the major components as collagen I and relaxed-fibronectin of ECM. Retinoic acid (RA) could disturb Golgi of CAFs, resulting in the reduction of protein secretion from the headstream. As expected, the strategy of RBC vesicles protected FnBPA5 targeting and RA-induced protein reduction was confirmed to reprogram the dense stroma and improve the penetration of Doxorubicin (Dox) in PDAC. RBC-Fn-NP inhibited tumor growth in both Pan02-orthotopic bearing model and Pan02-subcutaneous mice model. Hence, these partial ligand shielding nanoparticles offer a multifunctional and efficient approach to overcome penetration barriers and enhance the antitumor efficacy of chemotherapy in PDAC. STATEMENT OF SIGNIFICANCE: A partial ligand shielding nanoparticle platform (RBC-Fn-NP), which has the function of an RBC vesicle "shell" and thetargeting properties of a "core" to achieve superior therapeutic effects against PDAC, was established. The targeted ligand was modified on the surface of the nanoparticles instead of the RBC membranes. Three-dimensional PDAC stroma-rich spheroids were established to evaluate the penetration and tumor stroma remodeling. The targeting properties of FnBPA5 peptide, the effect of RA-induced Golgi disruption on the reduction of protein secretion, and the incomplete "camouflage" of the RBC vesicles were confirmed both in vitro and in vivo. As expected, our nanoplatform may provide a promising strategy for remolding dense stroma and enhancing the permeability in PDAC.