Biomaterial Strategies for Targeted Intracellular Delivery to Phagocytes

Abstract Phagocytes are essential for orchestrating both short‐ and long‐term immune responses by internalizing extracellular material to clear pathogens, resolve tissue damage, present antigens, and secrete regulatory cytokines. In chronic inflammation, however, phagocyte activity becomes dysregulated and can perpetuate disease. Current therapeutic approaches to inflammatory disease, including corticosteroids and biologics, are often limited by severe systemic side effects, lack of specificity, and high costs, underscoring the need for precise interventions. Particulate delivery systems offer a transformative solution, leveraging their biocompatibility, scalability, and customizable properties for immune modulation. These systems enable controlled drug release, site‐specific targeting, and the capacity to selectively influence phagocyte behavior through tailored size, shape, and surface modifications. In this review, the potential of particulate systems to revolutionize phagocyte‐targeted therapies is explored. By examining key design parameters including particle size, shape, surface chemistry, and material properties, and their interactions with immune cells, this review provides a comprehensive framework for optimizing technologies to achieve precision immune modulation. Emphasis is placed on how these design choices influence receptor engagement, uptake pathways (phagocytosis, macropinocytosis, receptor‐mediated endocytosis), intracellular trafficking, and immune polarization. Actionable design principles tailored to specific therapeutic goals, such as promoting tolerogenic responses for autoimmunity or fine‐tuning inflammatory resolution in chronic diseases are provided.