CD11b activated nanovesicles synergizing external defense against MDSCs and internal attack on tumor cells for enhanced chemo-immunotherapy of pancreatic cancer

Pancreatic cancer, characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells (MDSCs), leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy. A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer. Herein, a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1 (LA) and the polyamide-oxaliplatin (PAMAM-OXA) nanoparticles (P), named MLR/LA@P, was constructed for pancreatic cancer treatment. The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1, thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for “external defense”. In response to matrix metalloproteinase-2 (MMP2) in the tumor microenvironment, MLR/LA@P degraded and released small-sized P for deep penetration. Subsequently, OXA was released in response to glutathione within tumor cells, triggering immunogenic cell death for “internal attack”. MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors, but also prevented the formation of pre-metastatic niches (PMNs), which is promising for pancreatic cancer treatment.