Biomimetic Homotypic Nanoparticles Co-delivering Gemcitabine and IKKβ Inhibitor Reverse Gemcitabine induced Stemness for Enhanced Pancreatic Cancer Therapy

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with early metastasis, poor prognosis, and limited surgical eligibility. Chemotherapy, primarily gemcitabine (GEM), remains the standard treatment, but rapid development of GEM resistance partly driven by the induction of cancer stem cell (CSC)-like properties severely limits its efficacy. Aberrant activation of the IKKβ/NF-κB signaling pathway promotes CSC maintenance, tumor progression, and chemoresistance, suggesting that targeted inhibition could enhance GEM sensitivity. In this study, we developed a biomimetic nanoparticle system (84/PGEM@KPC) by loading the IKKβ inhibitor Analog 84 into GEM-based polymeric prodrug nanoparticles, followed by coating with KPC pancreatic cancer cell membranes to achieve homotypic targeting and immune evasion. The 84/PGEM@KPC nanoparticles exhibited a uniform size of about 20nm, a zeta potential around -20mV, and high drug loading and stability, achieving more efficient tumor penetration and accumulation than 84/PGEM. In vitro, these nanoparticles effectively reversed GEM induced stemness, suppressed NF-κB activation, and synergistically promoted apoptosis of pancreatic cancer cells. In vivo, treatment with 84/PGEM@KPC markedly inhibited PDAC growth, increased the infiltration of IFN-γ⁺ and Granzyme B⁺ CD8⁺ T cells, and reduced immunosuppressive regulatory T cells, demonstrating both potent antitumor efficacy and favorable immune modulation. Collectively, this dual functional nanoplatform integrates GEM prodrug delivery, IKKβ inhibition, and homotypic targeting to overcome chemoresistance and remodel the immune microenvironment, providing a promising strategy for enhanced pancreatic cancer therapy.