Co-evolving biomaterials: Spatiotemporally programmable materials steering dynamic macrophage state transitions

Macrophages are highly plastic innate immune cells that integrate metabolic, inflammatory, and stromal cues to coordinate immune responses and tissue repair. In biomaterial-associated microenvironments, these signals act together over time and shape macrophage trajectories through ongoing interactions with surrounding tissues. Most currently available immunomodulatory biomaterials are understood as static, stimulus-responsive, or partially adaptive systems, rather than systems that fully operate in a closed-loop manner. Against this background, this review organizes macrophage-material interactions within a stage-responsive framework. We relate the biological determinants of macrophage state transitions, including immunometabolism, regulated cell death and efferocytosis, and epigenetic remodeling, to three key dimensions of biomaterial design: timing, spatial control, and dose or sequence. In this review, co-evolving is used to describe a reciprocal, time-dependent process in which biomaterials influence macrophage behavior, while changes in the local microenvironment driven by macrophages in turn affect material behavior in vivo and shape downstream tissue outcomes. On this basis, we distinguish static, stimulus-responsive, and feedback-informed forms of immunomodulation, and discuss how future biomaterials may move toward more genuinely feedback-controlled interactions. STATEMENT OF SIGNIFICANCE: This review reframes immunomodulatory biomaterials through macrophage state transitions rather than fixed polarization labels. It proposes a stage-responsive framework linking key drivers of macrophage behavior, including immunometabolism, regulated cell death and efferocytosis, epigenetic remodeling, and tissue-niche crosstalk, to three design dimensions: timing, spatial control, and dose or sequence. Current strategies are classified as static, stage-programmed, stimulus-responsive, or feedback-informed, clarifying what existing materials can achieve and where true adaptive control remains limited. By integrating evidence from repair and disease contexts, the review provides a practical basis for designing biomaterials that better match macrophage transition kinetics and move toward stage-aware immune engineering.