Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy.

The PD1/PD-L1 immune checkpoint blocking is a promising therapy, while immunosuppressive tumor microenvironment (TME) and poor tumor penetration of therapeutic antibodies limit its efficacy. Repolarization of tumor-associated macrophages (TAMs) offers a potential method to ameliorate immunosuppression of TME and further boost T cell antitumor immunity. Herein, hybrid cell membrane biomimetic nanovesicles (hNVs) are developed by fusing M1 macrophage-derived nanovesicles (M1-NVs) and PD1-overexpressed tumor cell-derived nanovesicles (PD1-NVs) to improve cancer immunotherapy. The M1-NVs promote the transformation of M2-like TAMs to M1-like phenotype and further increase the release of pro-inflammatory cytokines, resulting in improved immunosuppressive TME. Concurrently, the PD1-NVs block PD1/PD-L1 pathway, which boosts cancer immunotherapy when combined with M1-NVs. In a breast cancer mouse model, the hNVs efficiently accumulate at the tumor site after intravenous injection and significantly inhibit the tumor growth. Mechanically, the M1 macrophages and CD8+ T lymphocytes in TME increase by twofold after the treatment, indicating effective immune activation. These results suggest the hNVs as a promising strategy to integrate TME improvement with PD1/PD-L1 blockade for cancer immunotherapy.

Zhao C ，Pan Y ，Liu L ，Zhang J ，Wu X ，Liu Y ，Zhao XZ ，Rao L ... -  《-》

Construction of Hierarchically Biomimetic Iron Oxide Nanosystems for Macrophage Repolarization-Promoted Immune Checkpoint Blockade of Cancer Immunotherapy.

Kang Y ，Yan J ，Han X ，Wang X ，Wang Y ，Song P ，Su X ，Rauf A ，Jin X ，Pu F ，Zhang H ... -  《-》

M1 Macrophage-Derived Nanovesicles Potentiate the Anticancer Efficacy of Immune Checkpoint Inhibitors.

Choo YW ，Kang M ，Kim HY ，Han J ，Kang S ，Lee JR ，Jeong GJ ，Kwon SP ，Song SY ，Go S ，Jung M ，Hong J ，Kim BS ... -  《-》

Genetically engineered cellular nanoparticles loaded with curcuminoids for cancer immunotherapy.

Background: Inducing immunogenic cell death (ICD) is a promising strategy to enhance immune responses for immune checkpoint blockade (ICB) therapy, but the lack of a simple and effective platform to integrate ICD and ICB therapy limits their clinical application. Methods: Here, we developed programmed cell death protein 1 (PD1)-overexpressing genetically engineered nanovesicles (NVs)-coated curcumin (Cur)-loaded poly (lactic-co-poly-polyglycolic acid) nanoparticles (PD1@Cur-PLGA) to integrate ICD and ICB therapy for enhancing tumor immunotherapy. Results: Genetically engineered NVs greatly enhanced the tumor targeting of nanoparticles, and the PD1 on NVs dramatically blocked the PD1/PDL1 signaling pathway and stimulated antitumor immune responses. Meanwhile, the delivered Cur successfully induced tumor cell apoptosis and activated ICD by inhibiting NF-κB phosphorylation and Bcl-2 protein expression and activating caspase and Bax apoptotic signaling. By synergizing the ICD effect of Cur and the PD1/PDL1 axis blocking function of genetically engineered NVs, the PD1@Cur-PLGA enhanced the intratumoral infiltration rate of mature dendritic cells and CD8+ T cells in tumor tissues, resulting in significantly inhibiting tumor growth in breast and prostate tumor-bearing mouse models. Conclusion: This synergistic ICD and ICB therapy based on genetically engineered NVs provides a low-cost, safe, and effective strategy to enhance cancer immunotherapy.

Liao Y ，Zhao C ，Pan Y ，Guo Y ，Liu L ，Wu J ，Zhang Y ，Rao L ，Li Q ... -  《Theranostics》

Genetically engineered PD-1 displaying nanovesicles for synergistic checkpoint blockades and chemo-metabolic therapy against non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the most frequently diagnosed lung cancer and the leading cause of cancer-related mortality worldwide. PD-1/PD-L1 axis inhibitors have changed the treatment paradigm for various cancer types, including NSCLC. However, success of these inhibitors in lung cancer clinic is severely limited by their inability to inhibit the PD-1/PD-L1 signaling axis due to heavy glycosylation and heterogeneity expression of PD-L1 in NSCLC tumor tissue. Taking advantage of the facts that tumor cell derived nanovesicles could efficiently accumulate in the homotypic tumor sites due to their innate targeting abilities and that specific and high affinity existed between PD-1 and PD-L1, we developed NSCLC targeting biomimetic nanovesicles (NV) cargos from genetically engineered NSCLC cell lines that overexpressed PD-1 (P-NV). We showed that P-NVs efficiently bound NSCLC cells in vitro and targeted tumor nodules in vivo. We further loaded P-NVs with 2-deoxy-D-glucose (2-DG) and doxorubicin (DOX), and found that these drugs co-loaded P-NVs efficiently shrank lung cancers in mouse models for both allograft and autochthonous tumor. Mechanistically, drug-loaded P-NVs efficiently caused cytotoxicity to tumor cells and simultaneously activated anti-tumor immunity function of tumor-infiltrating T cells. Our data therefore strongly argue that 2-DG and DOX co-loaded, PD-1-displaying nanovesicles is a highly promising therapy for treatment of NSCLC in clinic. STATEMENT OF SIGNIFICANCE: Lung cancer cells overexpressing PD-1 are developed for preparing nanoparticles (P-NV). PD-1s displayed on NVs enhance their homologous targeting abilities to tumor cells expressing PD-L1s. Chemotherapeutics such as DOX and 2-DG, are packaged in such nanovesicles (PDG-NV). These nanovesicles efficiently delivered chemotherapeutics to tumor nodules specifically. The synergy between DOX and 2-DG is observed in inhibiting lung cancer cells in vitro and in vivo. Importantly, 2-DG causes deglycosylation and downregulation of PD-L1 on tumor cells while PD-1 displayed on nanovesicles' membrane blocks PD-L1 on tumor cells. 2-DG loaded nanoparticles thus activate anti-tumor activities of T cells in the tumor microenvironment. Our work thus highlights the promising antitumor activity of PDG-NVs, which warrants further clinical evaluation.

Li B ，Yang T ，Liu J ，Yu X ，Li X ，Qin F ，Zheng J ，Liang J ，Zeng Y ，Zhou Z ，Liu L ，Zhang B ，Yao W ，Feng Z ，Zeng G ，Zhou Q ，Chen L ... -  《-》