Pancreatic cancer is a malignant disease with high mortality and poor prognosis due to lack of early diagnosis and low treatment efficiency after diagnosis. Although Gemcitabine (GEM) is used as the first-line chemotherapeutic drug, chemoresistance is still the major problem that limits its therapeutic efficacy. Here in this study, we developed a specific M1 macrophage-derived exosome (M1Exo)-based drug delivery system against GEM resistance in pancreatic cancer. In addition to GEM, Deferasirox (DFX) was also loaded into drug carrier, M1Exo, in order to inhibit ribonucleotide reductase regulatory subunit M2 (RRM2) expression via depleting iron, and thus increase chemosensitivity of GEM. The M1Exo nanoformulations combining both GEM and DFX significantly enhanced the therapeutic efficacy on the GEM-resistant PANC-1/GEM cells and 3D tumor spheroids by inhibiting cancer cell proliferation, cell attachment and migration, and chemoresistance to GEM. These data demonstrated that M1Exo loaded with GEM and DFX offered an efficient therapeutic strategy for drug-resistant pancreatic cancer.

The conversion of tumor-promoting M2 macrophage phenotype to tumor-suppressing M1 macrophages is a promising therapeutic approach for cancer treatment. However, the tumor normally provides an abundance of M2 macrophage stimuli, which creates an M2 macrophage-dominant immunosuppressive microenvironment. In our study, docetaxel (DTX) as chemotherapeutic modularity was loaded into M1 macrophage-derived exosomes (M1-Exo) with M1 proinflammatory nature to establish DTX-M1-Exo drug delivery system. We found that DTX-M1-Exo induced naïve M0 macrophages to polarize to M1 phenotype, while failed to repolarize to M2 macrophages upon Interleukin 4 restimulation due to impaired mitochondrial function. This suggests that DTX-M1-Exo can achieve long-term robust M1 activation in immunosuppressive tumor microenvironment. The in vivo results further confirmed that DTX-M1-Exo has a beneficial effect on macrophage infiltration and activation in the tumor tissues. Thus, DTX-M1-Exo is a novel macrophage polarization strategy via combined chemotherapy and immunotherapy to achieve great antitumor therapeutic efficacy.

Advanced breast cancer with recurrent and distal organ metastasis is aggressive and incurable. The current existing treatment strategies for advanced breast cancer are difficult to achieve synergistic treatment of recurrent tumors and distant metastasis, resulting in poor clinical outcomes. Herein, a synergistic therapy strategy composed of biomimetic tumor‐derived exosomes (TEX)‐Liposome‐paclitaxel (PTX) with lung homing properties and gold nanorods (GNR)‐PEG, was designed, respectively. GNR‐PEG, with well biocompatibility, cured recurrent tumors effectively by thermal ablation under the in situ NIR irradiation. Meanwhile, GNR‐mediated thermal ablation activated the adaptive antitumor immune response, significantly increased the level of CD8⁺ T cells in lungs and the concentration of serum cytokines (tumor necrosis factor‐α, interlekin‐6, and interferon‐γ). Subsequently, TEX‐Liposome‐PTX preferentially accumulated in lung tissues due to autologous tumor‐derived TEX with inherent specific affinity to lung, resulting in a better therapeutic effect on lung metastasis tumors with the assistance of adaptive immunotherapy triggered by GNR in vivo. The enhanced therapeutic efficacy in advanced breast cancer was a combination of thermal ablation, adaptive antitumor immunotherapy, and targeted PTX chemotherapy. Hence, the synergistic strategy based on GNR and TEX‐Liposome provides selectivity to clinical treatment of advanced breast cancer with recurrent and metastasis.