Rewiring Biological Barriers in Pancreatic Diseases with Metal–Organic Frameworks

Pancreatic diseases, particularly pancreatic ductal adenocarcinoma (PDAC), remain among the most challenging disorders to diagnose and treat owing to a series of interconnected biological barriers, including dense stromal desmoplasia, profound immunosuppression, hypoxia, therapeutic resistance, and the lack of effective early-detection strategies. Overcoming these barriers requires multifunctional platforms capable of integrating diagnosis, microenvironment regulation, and precision therapy within a single system. Metal–organic frameworks (MOFs), a class of highly tunable porous crystalline materials, have emerged as uniquely suited candidates for this purpose because of their programmable composition, structural versatility, catalytic activity, and capacity for multifunctional integration. Notably, MOFs have evolved from passive drug carriers into active regulators of disease-associated biological processes, enabling enhanced drug delivery, extracellular matrix remodeling, ferroptosis- and cuproptosis-based precision therapy, energy-triggered reactive oxygen species generation, immune microenvironment reprogramming, and imaging-guided theranostics. Beyond pancreatic cancer, emerging evidence further supports their potential applications in pancreatitis management and interventional therapeutic enhancement. In this review, we systematically summarize recent advances in the rational engineering of MOFs for pancreatic diseases, focusing on how material design strategies are leveraged to overcome key pathological barriers and improve therapeutic outcomes. We further discuss current challenges associated with biosafety, biodegradation, large-scale manufacturing, and clinical translation, while highlighting future opportunities for the development of next-generation MOF-based precision nanomedicines. By integrating advances across materials science, nanomedicine, and pancreatic disease biology, this review provides a comprehensive framework for the design and translational development of MOF-enabled diagnostic and therapeutic platforms.