In Situ Engineering Mesenchymal Stem Cells for Osteogenic Differentiation to Reverse Inflammaging and Restore Periodontal Bone Homeostasis

Abstract Chronic inflammatory diseases such as periodontitis pose significant challenges for regenerative therapies, particularly stem cell‐based approaches. Conventional ex vivo engineering strategies, in which nanoparticles or bioactive molecules are pre‐loaded onto mesenchymal stem cells (MSCs) prior to transplantation, often disrupt cell phenotype, limit therapeutic efficacy, and result in poor retention and engraftment at target sites. In this study, an innovative in situ engineering strategy involving the co‐delivery of MSCs with cerium–tannic acid@bovine serum albumin nanoparticles (CTB NPs) is introduced, which enables real‐time osteogenic differentiation within the inflammatory microenvironment. Unlike traditional methods, this in situ approach harnesses the intrinsic homing and adaptive responses of MSCs within pathological niches, achieving real‐time functional augmentation and precise biointerface modulation under inflammatory stress. This strategy increases MSC viability by 15%, enhances osteogenic differentiation by 70%, and reduces cellular senescence by 73.2%, as evidenced by decreased p21 expression. In a rat periodontitis model, CTB@MSCs markedly attenuate inflammation, reduce bone resorption by 56.25%, and restore alveolar bone height by 75%, demonstrating robust therapeutic potential in chronic inflammatory conditions. Collectively, this in situ MSC engineering platform offers a promising avenue for stem cell‐based treatment of periodontitis and other inflammatory diseases.