Rational Design of Engineered Bionic Periosteum for Dynamic Immunoinduction, Smart Bactericidal, and Efficient Bone Regeneration

Abstract Bone defects arising from trauma and tumors present a potential risk of infection and compromise host immune function. Within a dysfunctional microenvironment, the uncontrolled breeding of bacteria and persistent chronic inflammation exacerbate bone loss, impeding bone regeneration and repair. Macrophages function as specialized phagocytes within the immune microenvironment and the orchestrated role of distinct phenotypes during regeneration has attracted significant attention. The M1 phenotype exhibits antimicrobial activities to eliminate bacterial threats, while the M2 phenotype secretes anti‐inflammatory mediators to fine‐tune the immune microenvironment. Here, a biphasic delivery system consisting of a photothermal agent (graphene oxide, GO) coated and an immune modulator (urolithin A, UA) encapsulated in coaxial electrospun nanofibers with a dynamic regulation function of macrophage behavior is designed. It is observed that the GO coating exhibited remarkable photothermal performance within the near‐infrared window, affecting the phagocytic activity of macrophage subsets in an integrin‐RhoA‐ROCK1 dependent manner. The sustained release of UA from the core layer induced a phenotypic switch by downregulating TNF signaling and upregulating TGF signaling. This system also demonstrated a promotion of bone regeneration in vivo. Overall, this strategy achieved sequential regulation of macrophage phenotypes, effectively preventing infection and fostering bone tissue regeneration.