IL-4 and arginine synergy accelerates early bone regeneration via enhanced efferocytosis and ameliorated microenvironment

Apoptosis at bone defects drives an anti-osteogenic oxidative stress environment • IL-4 drives a pro-reparative macrophage phenotype and upregulates the Arg1 pathway • Exogenous Arg fuels efferocytosis and secretion of pro-regenerative factors • Co-delivery of IL-4 and Arg via injectable hydrogel accelerates bone regeneration Summary Host bone microenvironment is a critical factor for successful bone regeneration during implantation. In this work, we identified a spatiotemporal mismatch at drilling-induced injury sites where initial apoptosis outpaces macrophage recruitment, leading to apoptotic cell accumulation and oxidative stress that impairs osteogenic differentiation. To mitigate this phenomenon, we developed a synergistic strategy co-delivering interleukin 4 (IL-4) and arginine (Arg) to reprogram the microenvironment. Mechanistically, IL-4 recruits and polarizes macrophages toward a pro-reparative M2 phenotype, while Arg fuels the arginase-1 metabolic pathway to sustain continual efferocytosis and secretion of pro-regenerative cytokines. In a mouse bone injury model, transcriptomic and histological analyses confirmed that this strategy accelerates apoptotic clearance and establishes an M2-dominant environment, significantly enhancing early bone regeneration. Altogether, this work proposes a novel therapeutic paradigm targeting macrophage efferocytosis to resolve early microenvironmental imbalances, providing a promising therapeutic approach to promote bone defect healing and offering novel insights into optimizing host microenvironments for osseointegration following implantation. Download: Download high-res image (245KB) Download: Download full-size image