Gemcitabine-loaded nanoparticles for pancreatic cancer: from mechanistic innovations to clinical translation.

Pancreatic cancer encompasses a heterogeneous group of malignancies, of which pancreatic ductal adenocarcinoma (PDAC) represents the predominant histological subtype, accounting for over 90% of cases, and remains one of the most formidable challenges in oncology, marked by late diagnosis, aggressive progression, and profound resistance to conventional therapies. Despite gemcitabine's longstanding role as a first-line chemotherapeutic agent, its clinical efficacy is severely limited by rapid systemic degradation, poor tumor penetration, and a hostile tumor microenvironment (TME). This review synthesizes recent advances in nanotechnology-driven strategies to enhance gemcitabine delivery and efficacy in PDAC. It explores a spectrum of nanocarrier systems including polymeric, lipid-based, proteinaceous, inorganic, and biomimetic platforms that address pharmacokinetic and biological barriers through targeted delivery, controlled release, and microenvironment modulation. Special emphasis is placed on multifunctional and combination nanotherapies that co-deliver gemcitabine with agents targeting stromal remodeling, immune activation, gene silencing, metabolic reprogramming, and photothermal sensitization. These integrated approaches not only improve drug bioavailability and tumor specificity but also reprogram the immunosuppressive and fibrotic TME, offering a path toward more effective and personalized treatment paradigms. Collectively, the reviewed innovations underscore the transformative potential of nanomedicine in redefining therapeutic outcomes for PDAC, a malignancy long considered intractable.