Immunomodulatory Biomaterials: Principles, Immune Engineering Strategies, and Emerging Applications in Regenerative Medicine.

Biomaterials have undergone a remarkable transformation from passive structural components to bioactive therapeutic platforms capable of regulating complex biological processes and orchestrating host immune responses. This review provides a comprehensive overview of the fundamental principles, recent advances, and future perspectives of immunomodulatory biomaterials, emphasizing their expanding role in regenerative medicine and therapeutic applications. Initially, the major classes of biomaterials, including metallic, ceramic, polymeric, and composite systems, are systematically examined with respect to their physicochemical characteristics, biological functions, advantages, limitations, and clinical relevance. The review further explores the molecular and cellular mechanisms underlying biomaterial-host interactions, including protein adsorption, cell adhesion, mechanotransduction, immune activation, foreign body responses, biofilm formation, and tissue integration. Particular emphasis is placed on the emerging concept of immunoengineering, highlighting how biomaterial properties such as surface chemistry, topography, stiffness, degradation behavior, and biofunctionalization can regulate innate and adaptive immune responses through macrophage polarization, dendritic cell activation, and T-cell modulation. Recent developments in smart and stimuli-responsive biomaterials, nanotechnology, surface engineering, extracellular matrix-inspired systems, and bioactive molecule delivery are critically discussed for their ability to create pro-regenerative immune microenvironments and enhance therapeutic efficacy. Furthermore, current and emerging applications in tissue engineering, wound healing, controlled drug delivery, cancer immunotherapy, vaccine development, and personalized medicine are reviewed to demonstrate the broad translational potential of next-generation biomaterials. Finally, key challenges associated with long-term biocompatibility, immune variability, biodegradation, infection control, regulatory standardization, manufacturing scalability, and clinical translation are critically evaluated. By integrating advances in materials science, immunology, nanotechnology, and bioengineering, this review highlights immunomodulatory biomaterials as intelligent therapeutic platforms that actively direct immune responses and offers future perspectives for the rational design of personalized and clinically translatable biomaterial systems.