Leukemia Cell Hitchhiking Hypoxia Responsive Nanogel for Improved Immunotherapy of Acute Myeloid Leukemia

Abstract Immune checkpoint blockade (ICB) with anti‐CD47 antibodies (aCD47) is a promising therapeutic approach that has the potential to revolutionize the treatment of acute myeloid leukemia (AML). However, the low immune response rate and high systemic hematotoxicity remain substantial barriers to its success in clinical AML treatment. A synthetic protein nanogel formulation of aCD47 and resiquimod (R848) (termed CR‐TNG) is developed that targets TIM‐3 on the surface of leukemia cells. Upon intravenous injection, the CR‐TNG efficiently conjugates onto the blood‐circulating leukemia cells and migrates toward the bone marrow (BM) by exploiting the natural BM homing capability of leukemia cells. CR‐TNG releases aCD47 and R848 in a bone marrow hypoxic microenvironment, which significantly induces immunosuppression and enhances the anti‐leukemia immune response by activating macrophage “eat me” signaling and priming myeloid macrophages in the BM niche. These findings provide a leukemia cell‐hitchhiking drug delivery strategy that addresses both systemic hematotoxicity and low immune response rate in AML.