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.