Immune-epigenetic convergence in biomaterial-guided tissue regeneration

Biomaterials-driven immunomodulation and epigenetic regulation are increasingly recognized as key determinants of cell behavior and regenerative outcomes, yet they have largely been studied independently. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, regulate gene expression, cellular plasticity, and lineage commitment in response to biomaterial cues. Meanwhile, immune responses, particularly macrophage polarization and the foreign body response, critically influence the inflammatory and regenerative microenvironment after biomaterial implantation. However, regenerative outcomes are rarely governed by either mechanism in isolation. Epigenetic regulation and immune responses are tightly coupled during host-material interactions, so controlling one axis without addressing the other may limit the ability to achieve long-term success. Emerging evidence indicates that these processes are mutually reinforcing, forming a coupled regulatory system in which inflammatory signals reshape the epigenome, whereas epigenetic states regulate how immune cells perceive and respond to environmental cues. Notably, key biomaterial properties such as stiffness, topography, wettability, biochemical composition, and degradability can act as convergent upstream regulators that simultaneously regulate epigenetic states and immune responses, yet this intersection remains largely unexplored. This review systematically summarizes recent advances in biomaterials-driven epigenetic regulation and immunomodulation, emphasizing the emerging immune-epigenetic convergence in tissue regeneration. By integrating current knowledge with proposed design strategies, we establish a framework for engineering biomaterials that coordinate immune and epigenetic regulation to achieve more predictable and durable regenerative outcomes.