Synergistic Regulation of Biomaterials and Macrophages: A Novel Paradigm in Immunotherapy

Abstract

Macrophages have emerged as central regulators of tissue homeostasis, inflammation, and regeneration, yet their remarkable phenotypic plasticity and functional heterogeneity pose substantial challenges for therapeutic modulation. This review provides a comprehensive synthesis of macrophage immunobiology and its translation into bioengineered material strategies for cancer immunotherapy, anti‐infective/inflammatory therapy, and tissue regeneration. We first delineate the ontogeny and functional specialization of tissue‐resident and tumor‐associated macrophage populations, the marker‐defined subpopulations revealed by single‐cell technologies, and the signaling networks that govern macrophage polarization. We further examine the complex crosstalk between macrophages and the microenvironment, encompassing interactions with tumor cells, fibroblasts, neutrophils, and T cells, as well as metabolic regulation by lactate, cAMP, exosomes, and trained immunity. Building on this mechanistic foundation, we systematically review bioengineered delivery platforms spanning nanoscale carriers, cell membrane‐coated biomimetic systems, surface‐functionalized particles, and macroscale hydrogels and scaffolds, emphasizing the bidirectional macrophage–material feedback that dictates therapeutic outcomes. Despite notable progress, challenges in macrophage heterogeneity, manufacturing scalability, and long‐term safety remain. We highlight emerging directions, including single‐cell and spatial transcriptomics‐guided design, trained immunity‐based strategies, and artificial intelligence‐driven material development, which together promise to accelerate the translation of macrophage‐targeting biomaterials from bench to bedside.