A novel anti-CD47 protein antibody and toll-like receptor agonist complex detects tumor surface CD-47 changes in early stage lung cancer by in vivo imaging.

CD47, a cell surface protein known for inhibiting phagocytosis, plays a critical role in the tumor microenvironment (TME) and is a potential biomarker for cancer. However, directly applying αCD47, a hydrophilic macromolecular antibody that targets CD47, in vivo for cancer detection can have adverse effects on normal cells, cause systemic toxicities, and lead to resistance against anti-cancer therapies. In this study, we developed a novel complex incorporating aluminum-based metal-organic frameworks (Al-MOF) loaded with indocyanine green (ICG), αCD47, and resiquimod (R848), a hydrophobic small molecule Toll-like receptor 7/8 (TLR7/8) agonist. Upon activation with an infrared 808 nm laser, the nanocomposites exhibited photothermal effects that triggered the release of the loaded reagents, induced ROS production, and induced changes in the TME. This led to the polarization of immune-suppressive M2 macrophages towards an immune-stimulatory M1 phenotype, promoted dendritic cell (DC) maturation, and enabled mature DCs to facilitate antigen presentation, T-cell activation, and critical roles in tumor immunity. Furthermore, in vivo imaging successfully detected the specific binding of αCD47 with CD47 on tumor cells. Overall, the complex composed of αCD47 antibody and toll-like receptor agonist showed promising efficacy in both tumor diagnosis and therapy, providing a potential strategy for detecting early lung cancer and modulating the tumor microenvironment for improved treatment outcomes.

Xu Y ，Gu L ，Zhu L ，Miao Y ，Cui X ... -  《-》

Nanoscale Metal-Organic Framework Co-delivers TLR-7 Agonists and Anti-CD47 Antibodies to Modulate Macrophages and Orchestrate Cancer Immunotherapy.

Ni K ，Luo T ，Culbert A ，Kaufmann M ，Jiang X ，Lin W ... -  《-》

Supermolecular nanovehicles co-delivering TLR7/8-agonist and anti-CD47 siRNA for enhanced tumor immunotherapy.

Shang T ，Yu X ，Gu Y ，Du R ，Cai Y ，Li Y ，Zheng G ，Wang C ，Zhang J ，Liu J ，Han S ，Yang B ... -  《-》

Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment.

With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa. The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.

Lin W ，Li C ，Xu N ，Watanabe M ，Xue R ，Xu A ，Araki M ，Sun R ，Liu C ，Nasu Y ，Huang P ... -  《-》

Tumor microenvironment-responsive macrophage-mediated immunotherapeutic drug delivery.

Immunotherapy, as a promising treatment strategy for cancer, has been widely employed in clinics, while its efficiency is limited by the immunosuppression of tumor microenvironment (TME). Tumor-associate macrophages (TAMs) are the most abundant immune cells infiltrating the TME and play a crucial role in immune regulation. Herein, a M0-type macrophage-mediated drug delivery system (PR-M) was designed for carrying Toll-like receptors (TLRs) agonist-loaded nanoparticles. When TLR agonist R848 was released by responding to the TME, the PR-Ms were polarized from M0-type to M1-type and TAMs were also stimulated from M2-type to M1-type, which eventually reversed the immunosuppressive states of TME. By synergizing with the released R848 agonists, the PR-M significantly activated CD4+ and CD8+ T cells in the TME and turned the 'cold' tumor into 'hot' tumor by regulating the secretion of cytokines including IFN-γ, TNF-α, IL-10, and IL-12, thus ultimately promoting the activation of antitumor immunity. In a colorectal cancer mouse model, the PR-M treatment effectively accumulated at the tumor site, with a 5.47-fold increase in M1-type and a 65.08 % decrease in M2-type, resulting in an 85.25 % inhibition of tumor growth and a 87.55 % reduction of tumor volume compared with the non-treatment group. Our work suggests that immune cell-mediated drug delivery systems can effectively increase drug accumulation at the tumor site and reduce toxic side effects, resulting in a strong immune system for tumor immunotherapy. STATEMENT OF SIGNIFICANCE: The formation of TME and the activation of TAMs create an immunosuppressive network that allows tumor to escape the immune system and promotes its growth and spread. In this study, we designed an M0-type macrophage-mediated drug delivery system (PR-M). It leverages the synergistic effect of macrophages and agonists to improve the tumor immunosuppressive micro-environment by increasing M1-type macrophages and decreasing M2-type macrophages. As part of the treatment, the drug-loaded macrophages endowed the system with excellent tumor targeting. Furthermore, loading R848 into TME-responsive nanoparticles could protect macrophages and reduce the potential toxicity of agonists. Further investigations demonstrated that the designed PR-M could be a feasible strategy with high efficacy in tumor targeting, drug loading, autoimmunity activation, and lower side effects.

Zhang X ，Yue L ，Cao L ，Liu K ，Yang S ，Liang S ，Liu L ，Zhao C ，Wu D ，Wang Z ，Tian R ，Rao L ... -  《-》