Responsive nanomedicine strategies achieve pancreatic cancer precise theranostics.

Pancreatic ductal adenocarcinoma (PDAC), the predominant subtype of pancreatic cancer, ranks among the deadliest malignancies worldwide, with a 5-year survival rate remaining below 13 %. Its poor prognosis stems from complex anatomical barriers, a dense and heterogeneous tumor microenvironment (TME), and intricate molecular regulatory networks that collectively hinder early detection and limit therapeutic efficacy. Nanomedicine offers promising solutions by enhancing drug loading, improving delivery, counteracting drug resistance, and enabling stimuli-responsive control. Notably, stimuli-responsive nanotherapeutics have emerged as a transformative strategy, achieving precise drug release through activation by endogenous TME cues (e.g., acidic pH, redox gradients, hypoxia, enzyme overexpression) or exogenous triggers (e.g., ultrasound, light, magnetic fields). Endogenous-responsive systems autonomously activate at tumor sites, enhancing intratumoral drug accumulation and reducing off-target effects, while exogenous-responsive platforms enable spatiotemporal control through external modulation. Multi-responsive systems integrate both mechanisms to achieve dynamic and synergistic therapeutic effects, holding significant promise for PDAC theranostics. This review summarizes recent advances in stimuli-responsive nanotherapeutics for PDAC, detailing their activation mechanisms, biomedical applications, and theranostic potential across endogenous, exogenous, and multi-responsive modalities. It further discusses current challenges and future directions for translating these technologies into clinical practice.