Posted by Pancreatic cancer (PC) is a highly lethal and aggressive malignancy, currently one of the leading causes of cancer-related deaths worldwide, in both women and men. PC is highly resistant to standard chemotherapy (CT) because its immunosuppressive and hypoxic tumor microenvironment and a dense desmoplastic stroma compartment extensively limit drug accessibility and perfusion. Although CT is one of the main therapeutic strategies for PC management contributing to tumor eradication through a cytotoxic effect, CT is associated with a poor pharmacokinetic profile and provokes deleterious systemic toxicity. This low efficacy-poor safety scenario urgently calls for innovative and highly specific therapeutic strategies to counteract this urgent clinical challenge. Nanotechnology-based precision materials for cancer may help improve drug stability and minimize the systemic cytotoxic effects by increasing drug tumor accumulation and also enabling controlled release, but several drawbacks still persist, such as the poor targeting efficiency. In the last few years increased attention has been paid to bioinspired nanosystems that can mimic either partially or totally biological systems, including lipid layers as suitable stealth coatings resembling the composition of cell membranes, lipoprotein- and blood protein-based nanosystems, and cell membrane-derived systems, such as extracellular vesicles, cell membrane nanovesicles and cell membrane-coated nanosystems, which display intrinsic cancer-targeting abilities, enhanced biocompatibility, decreased immunogenicity, and prolonged blood circulation profile. This review covers the recent breakthroughs on advanced biomimetic PC-targeted nanosystems, focusing on their design, properties and applications as innovative, multifunctional and versatile tools paving the way to improved PC diagnosis and treatment.
An example on CD-based nanosystem: Gemcitabine (GEM) and erlotinib were co-loaded with siRNA for stroma normalization and synergistic anticancer action of GEM and erlotinib. GEM was loaded by chemical conjugation to polycation PEI through disulfide bond (−ss-), which was then coupled to β-cyclodextrin (β-CD); the latter employed for loading erlotinib (ERL) in the hydrophobic cavity. PEI enabled direct complexation with IRAK4 siRNA (siIRAK4) through electrostatic interactions, assembling a final nanostructured core GEM-ss-PEI@siIRAK4-β-CD@ERL coated with hybrid cancer-macrophage cell membrane (siIRAK4/Er@GEM-SS-PC-M, in which PC represents PEI-β-CD, and M the hybrid cell membrane coating)
(A) Schematic illustration of siIRAK4/Er@GEM-ss-PC-M. GEM was conjugated to PC by a GSH-responsive linker to form a GEM prodrug, followed by encapsulating the Erlotinib (Er) via host–guest molecular interaction and loading with the IRAK4 siRNA to assemble cell membrane-coated NPs (siIRAK4/Er@GEM-ss-PC-M).
(B) Schematic illustration of targeted delivery of multidrug-loaded siIRAK4/Er@GEM-ss-PC-M.
Miguel Pereira-Silva, Francisco Veiga, Ana Cláudia Paiva-Santos, Angel Concheiro, Carmen Alvarez-Lorenzo (2025) Biomimetic nanosystems for pancreatic cancer therapy: A review. Journal of Controlled Release 383, 113824. https://doi.org/10.1016/j.jconrel.2025.113824