Photosynthetic Bacteria-Hitchhiking 2D iMXene-mRNA Vaccine to Enable Photo-Immunogene Cancer Therapy.

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor-associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co-deliver a tumor-associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene-WT1 mRNA to the core tumor region using photo-driven and hypoxia-driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo-immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

The existence of inadequate ablation remains an important cause of treatment failure for loco-regional ablation therapies. Here, using a preclinical model, it is reported that inadequate microwave ablation (iMWA) induces immunosuppressive niche predominated by myeloid cells. The gene signature of ablated tumor presented by transcriptome analyses is highly correlated with immune checkpoint blocking (ICB) resistance. Thus, an in situ scaffold with synergistic delivery of IPI549 and anti-programmed death-ligand 1 blocking antibody (aPDL1) for postablative cancer immunotherapy is designed and engineered, in which IPI549 capable of targeting myeloid cells could disrupt the immunosuppressive niche and subsequently improve ICB-mediated antitumor immune response. Based on five mouse cancer models, it is demonstrated that this biomaterial system (aPDL1&IPI549@Gel) could mimic a "hot" tumor-immunity niche to inhibit tumor progression and metastasis, and protect cured mice against tumor rechallenge. This work enables a new standard-of-care paradigm for the immunotherapy of myeloid cells-mediated "cold" tumors after loco-regional inadequate practices.

Tailoring Chemoimmunostimulant Bioscaffolds for Inhibiting Tumor Growth and Metastasis after Incomplete Microwave Ablation.

Microwave ablation has attracted the most attention as a locoregional therapeutic method for solid neoplasms. However, the high incidence of incomplete ablation that could promote the rapid cancer progression still remains a challenge in clinic. Herein, we found that the high invasiveness of residual tumor following incomplete microwave ablation (iMWA) is mainly due to the myeloid cell-mediated immunosuppression. Accordingly, we develop a biohydrogel scaffold-enabled chemoimmunotherapeutic strategy by targeting myeloid cells with a phosphoinositide 3-kinase γ (PI3Kγ) inhibitor (IPI549) to synergize with immunostimulatory chemotherapy (Oxaliplatin, OX) for post-ablative cancer therapy. With several tumor mouse models, we reveal that OX&IPI549@Gel-based localized chemoimmunotherapy can substantially suppress the growth of tumor post-iMWA, simultaneously evoke robust systemic anticancer immunity to inhibit metastatic spread, and offer strong long-term immunological memory functions against tumor rechallenge. Besides, this work proposes a potential opportunity for precision medicine by utilizing a mechanism-based rationale to the adoption of our pre-existing arsenal of anticancer immunotherapeutic schedule.