Macrophage-Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8(+) T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly(lactic-co-glycolic acid)(PLGA), which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-beta(TGF-beta), and Lnterleukin-10(IL-10), thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8(+) T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8(TLR7/8) agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.