Biomimetic Iron-Based Nanoparticles Remodel Immunosuppressive Tumor Microenvironment for Metabolic Immunotherapy.

Immunotherapy has led to a paradigm shift in reinvigorating treatment of cancer. Nevertheless, tumor associated macrophages (TAMs) experience functional polarization on account of the generation of suppressive metabolites, contributing to impaired antitumor immune responses. Hence, metabolic reprogramming of tumor microenvironment (TME) can synergistically improve the efficacy of anti-tumor immunotherapy. Herein, we engineered an iron-based nanoplatform termed ERFe3O4 NPs. This platform features hollow Fe3O4 nanoparticles loaded with the natural product emodin, the outer layer is coated with red blood cell membrane (mRBCs) inserted with DSPE-PEG2000-galactose. This effectively modulates lactate production, thereby reversing the tumor immune suppressive microenvironment (TIME). The ERFe3O4 NPs actively targeted TAMs on account of their ability to bind to M2-like TAMs with high expression of galectin (Mgl). ERFe3O4 NPs achieved efficient ability to reverse TIME via the production of reducing lactate and prompting enrichment iron of high concentrations. Furthermore, ERFe3O4 NPs resulted in heightened expression of CD16/32 and enhanced TNF-α release, indicating promotion of M1 TAMs polarization. In vitro and in vivo experiments revealed that ERFe3O4 NPs induced significant apoptosis of tumor cells and antitumor immune response. This study combines Traditional Chinese Medicine (TCM) with nanomaterials to synergistically reprogram TAMs and reverse TIME, opening up new ideas for improving anti-tumor immunotherapy.

Zhang W ，Li L ，Wu Y ，Li C ，Xu Z ，Zhang N ，Wang X ，Zhao Y ，Zu T ，He Q ，Jiao J ，Zheng R ... -  《International Journal of Nanomedicine》

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 ... -  《-》

Multifunctional biomimetic nanoparticles loading baicalin for polarizing tumor-associated macrophages.

Han S ，Wang W ，Wang S ，Wang S ，Ju R ，Pan Z ，Yang T ，Zhang G ，Wang H ，Wang L ... -  《-》

Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes.

Background: Among the many immunosuppressive cells in the tumor microenvironment, tumor-associated-macrophages (TAMs) are well known to contribute to tumor development. TAMs can be conditioned (polarized) to transition between classical M1-like macrophages, or alternatively to M2-like macrophages. Both are regulated by signaling molecules in the microenvironment. M1-like TAMs can secrete classic inflammatory cytokines that kill tumors by promoting tumor cell necrosis and immune cell infiltration into the tumor microenvironment. In contrast, M2-like TAMs exhibit powerful tumor-promoting functions, including degradation of tumor extracellular matrix, destruction of basement membrane, promotion of angiogenesis, and recruitment of immunosuppressor cells, all of which further promote tumor progression and distal metastasis. Therefore, remodeling the tumor microenvironment by reversing the TAM phenotype will be favorable for tumor therapy, especially immunotherapy. Methods: PLGA nanoparticles encapsulating baicalin and melanoma antigen Hgp peptide fragment 25-33 were fabricated using the ultrasonic double-emulsion technique. The nanoparticles were further loaded with CpG fragments and used conjugated M2pep and α-pep peptides on their surfaces to produce novel nano-complexes. The capability to target M2-like TAMs and anti-tumor immunotherapy effects of nano-complexes were evaluated by flow cytometry and confocal microscopy in vitro. We also investigated the survival and histopathology of murine melanoma models administrated with different nanocomplexes. Improvements in the tumor microenvironment for immune attack of melanoma-bearing mice were also assessed. Results: The nano-complexes were effectively ingested by M2-like TAMs in vitro and in vivo, and the acidic lysosomal environment triggered the disintegration of polydopamine from the nanoparticle surface, which resulted in the release of the payloads. The released CpG played an important role in transforming the M2-like TAMs into the M1-like phenotype that further secreted inflammatory cytokines. The reversal of TAM released cytokines and gradually suppressed tumor angiogenesis, permitting the remodeling of the tumor microenvironment. Moreover, the activated TAMs also presented antigen to T cells, which further stimulated the antitumor immune response that inhibited tumor metastasis. Activated T cells released cytokines, which stimulated NK cell infiltration and directly resulted in killing tumor cells. The baicalin released by M1-like TAMs also killed tumor cells. Conclusion: The nano-complexes facilitated baicalin, antigen, and immunostimulant delivery to M2-like TAMs, which polarized and reversed the M2-like TAM phenotype and remodeled the tumor microenvironment to allow killing of tumor cells.

Han S ，Wang W ，Wang S ，Yang T ，Zhang G ，Wang D ，Ju R ，Lu Y ，Wang H ，Wang L ... -  《Theranostics》

Immunomodulation of Tumor Microenvironment by Arginine-Loaded Iron Oxide Nanoparticles for Gaseous Immunotherapy.

Wu X ，Cheng Y ，Zheng R ，Xu K ，Yan J ，Song P ，Wang Y ，Rauf A ，Pan Y ，Zhang H ... -  《-》