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.