Engineered Xenogeneic Bone Scaffold with IL‐10 Nanodelivery System: Immunomodulation and BMSC Fate Programming for Skull Defect Repair

Skull defect reconstruction remains clinically challenging because current artificial implants lack bioactivity and produce radiological artifacts, whereas autologous bone grafts suffer from unpredictable resorption and infection. Here, we developed a multifunctional composite integrating antigen‐extracted xenogeneic scaffold, IL‐10‐loaded mesoporous polydopamine nanoparticles (MPDA@IL‐10), and autologous bone marrow‐derived mesenchymal stem cells (BMSCs). The composite establishes a temporally phased immunoregulatory axis: nanoparticle‐delivered exogenous IL‐10 compresses the early inflammatory window, and BMSCs then secrete endogenous anti‐inflammatory factors that prevent scaffold resorption and maintain a pro‐regenerative milieu. Beyond immunomodulation, IL‐10 acts as a lineage‐determining cue, activating PI3K‐Akt/Wnt signaling to drive BMSC osteogenic commitment and suppress adipogenic drift at the early differentiation stage. In a canine critical‐sized skull defect model, this strategy markedly enhanced radiographic and histological regeneration. By uniting temporal immune modulation with stem cell fate programming, this approach offers a translatable route to skull repair.