Targeted drug delivery systems for pancreatic cancer therapy: advances, challenges, and future perspectives

The review summarizes recent advances, challenges, and future perspectives in targeted drug delivery systems (DDSs) for pancreatic cancer (PC) therapy. Given the dismal prognosis of PC treatment is hindered by a dense desmoplastic stroma, profound hypoxia, limited T-cell infiltration, and abundant immunosuppressive myeloid populations, together forming physical and immunological barriers to effective therapy. Targeted DDSs based on organic, inorganic, and biological platforms (e.g., liposomes/lipid nanoparticles, polymeric nanoparticles, carrier-free drug self-assembly systems, hybrid inorganic-organic nanomaterials, and biomimetic carriers such as exosomes and protein nanocages) can enhance tumor accumulation and reduce off-target toxicity through active ligand-receptor targeting, microenvironment-adaptive delivery, and controlled release triggered by internal cues (pH, enzymes, reactive oxygen species, hypoxia) or external stimuli (light, heat, magnetic fields). Importantly, DDSs are designed to remodel the immunosuppressive tumor microenvironment (TME) by reprogramming tumor-associated macrophages, inhibiting myeloid-derived suppressor cells, activating innate immune sensing pathways, and overcoming stromal immune exclusion via stroma-immune co-modulation or transcytosis-enabled penetration. We further discuss precision-medicine opportunities, proposing biomarker-guided stratification and monitoring frameworks that link patient-specific TME features (e.g., stroma-high/immune-excluded, myeloid-dominant, weak innate priming) to rational DDS selection and combination regimens. Future development should prioritize clinically actionable combination strategies, localized/depot delivery when appropriate, and data-driven design and optimization (including artificial intelligence and machine learning) to accelerate personalized, translatable DDSs for improving pancreatic cancer outcomes.