Differentiation Responsive Architected Macrophage (DREAM) Selectively Modulate Tumor Microenvironment for Cancer Immunotherapy

Abstract Immune checkpoint blockade (ICB) therapies have transformed the management of metastatic and advanced malignancies. A novel therapeutic paradigm targeting CD47 has emerged as a promising approach to enhance macrophage‐mediated tumor phagocytosis; however, systemic toxicity stemming from nonspecific antibody distribution remains a critical clinical challenge. To address this limitation, a modular nanoparticle system, termed Differentiation Responsive Architected Macrophage (DREAM), was engineered to exploit intrinsic macrophage homing for tumor‐specific co‐delivery of anti‐CD47 antibodies (aCD47) and Resiquimod (R848). This platform circumvents reliance on tumor microenvironment‐derived matrix metalloproteinase‐9 (MMP‐9) by utilizing autocrine MMP‐9 secretion to initiate spatially controlled drug release, while simultaneously amplifying protease production via dynamic macrophage differentiation. In vitro analyses demonstrated stimulus‐responsive payload dissociation kinetics. In vivo evaluation in murine tumor models revealed that systemic DREAM administration induced robust tumor regression following three treatment cycles, concomitant with a shift in immune microenvironment polarization from an immunosuppressive to pro‐inflammatory phenotype. By integrating autonomous activation mechanisms with cell‐specific targeting, this strategy establishes a macrophage‐centric delivery platform that enhances therapeutic precision, mitigates off‐tissue toxicity, and augments antitumor efficacy, thereby advancing the translational potential of next‐generation ICB modalities.