Targeting Inflammaging: A Metformin‐Releasing Titanium Implant Reprograms Senescent Macrophages to Orchestrate Angiogenesis and Osteogenesis

ABSTRACT Bone defect repair in elderly patients is frequently compromised by reduced osteogenic capacity and delayed healing. Chronic inflammation‐driven inflammaging is a critical contributor to this impairment, characterized by dysfunctional autophagy in senescent macrophages (S‐MΦs), excessive reactive oxygen species (ROS) accumulation, and persistent proinflammatory M1 polarization. These factors ultimately disrupt the essential coupling between angiogenesis and osteogenesis. Herein, we investigated whether metformin‐mediated autophagy induction could restore intracellular homeostasis in S‐MΦs to reestablish a regenerative osteoimmune microenvironment. To achieve this locally, we engineered a titanium (Ti)‐based coating system for sustained metformin delivery. We found that 0.1 mM metformin restored S‐MΦ homeostasis by enhancing autophagy (about 1‐fold higher autophagosome fluorescence) and reducing oxidative stress (about 50% lower ROS), thereby promoting prohealing M2 polarization, with about 40% higher CD206 and 70% lower iNOS expression. Consequently, the microenvironment modulated by rejuvenated S‐MΦs significantly alleviated oxidative stress in senescent endothelial cells (S‐ECs) and osteoblasts (S‐OBs), recovering their angiogenic and osteogenic functions. Material‐wise ordered titanium dioxide nanotubes (TNTs) were functionalized with layer‐by‐layer polydopamine (PDA) to enable efficient metformin loading and controlled release. This functionalized surface supported S‐MΦ viability and favorable morphology. Current mechanistic validation via exogenous stimulation and conditioned media, combined with the coating’s controllable drug release and biocompatibility, offers a promising strategy to enhance Ti implant integration in the context of aging‐associated immune dysfunction.