Functional Delivery of Nanoimmunotherapies in Pancreatic Ductal Adenocarcinoma: A Barrier-Informed Pharmaceutics Framework

Pancreatic ductal adenocarcinoma (PDAC) presents a stringent drug-delivery environment in which tumor accumulation does not necessarily translate into target-cell exposure or cargo activity. This critical narrative review develops a barrier-informed framework for evaluating nanoimmunotherapies across systemic exposure, tumor access, target-cell delivery, cargo release, target engagement, and pharmacological activity. The framework links vascular, stromal, immune, metabolic, and intracellular barriers to cargo-carrier selection, administration route, biological identity, pharmacokinetics, biodistribution, and intracellular trafficking. Platforms discussed include nanovaccines and nucleic-acid therapeutics, engineered extracellular vesicles, nanoengineered oncolytic-virus delivery, nanoparticle-assisted immune-cell programming, checkpoint modulation, and stromal or metabolic strategies relevant to immune-directed therapy. Functional-delivery evidence is integrated with critical quality attributes, mechanism-based potency, manufacturing comparability, biosafety, repeat-dose performance, and biomarker-guided clinical development. We propose a qualitative stage-gating framework based on concordant evidence of target-site exposure, target-cell activity, reproducible product quality, acceptable repeat-dose performance, and a testable biomarker strategy. This framework supports formulation selection, cross-platform comparison, and translational prioritization of PDAC nanoimmunotherapies.