Engineering Endogenous Tumor‐Associated Macrophage‐Targeted Biomimetic Nano‐RBC to Reprogram Tumor Immunosuppressive Microenvironment for Enhanced Chemo‐Immunotherapy

Abstract Immunotherapy has shown encouraging results in various cancers, but the response rates are relatively low due to the complex tumor immunosuppressive microenvironment (TIME). The presence of tumor‐associated macrophages (TAMs) and tumor hypoxia correlates significantly with potent immunosuppressive activity. Here, a hemoglobin–poly(ε‐caprolactone) (Hb–PCL) conjugate self‐assembled biomimetic nano red blood cell (nano‐RBC) system (V(Hb)) is engineered to deliver chemotherapeutic doxorubicin (DOX) and oxygen for reprogramming TIME. The Hb moiety of V(Hb)@DOX can bind to endogenous plasma haptoglobin (Hp) and specifically target the M2‐type TAMs via the CD163 surface receptor, and effectively kill the cells. In addition, the O₂ released by the Hb alleviates tumor hypoxia, which further augments the antitumor immune response by recruiting fewer M2‐type macrophages. TAM‐targeting depletion and hypoxia alleviation synergistically reprogram the TIME, which concurrently downregulate PD‐L1 expression of tumor cells, decrease the levels of immunosuppressive cytokines such as IL‐10 and TGF‐β, elevate the immunostimulatory IFN‐γ, enhance cytotoxic T lymphocyte (CTL) response, and boost a strong memory response. The ensuing TAM‐targeted chemo‐immunotherapeutic effects markedly inhibit tumor metastasis and recurrence. Taken together, the engineered endogenous TAM‐targeted biomimetic nano‐RBC system is a highly promising tool to reprogram TIME for cancer chemo‐immunotherapy.