Postnatal Maxillofacial “Developing” dECM Orchestrates Hierarchical Cross-organ Regeneration via Macrophage Integrin αvβ5-Mediated Efferocytosis-Driven Developmental Recapitulation

Decellularized extracellular matrix (dECM) leverages native architecture and bioactive components for tissue regeneration, yet its therapeutic efficacy is constrained by donor tissue maturity. While mature-tissue-derived dECM (Mat-dECM) lacks developmental signals, developmental-stage dECM (Dev-dECM) retains these cues but is limited by scarce sources and poor adaptability to adult environments. Here, we proposed postnatal maxillofacial odontogenic tissues as a novel Dev-dECM (pDev-dECM) source. Leveraging its unique trans-stage development—spanning embryonic crown formation to postnatal periodontal maturation—pDev-dECM balances developmental potency with adult environment adaptability. Multiomics comparative analysis revealed that pDev-dECM is enriched in arginylglycylaspartic-acid-containing proteins, which activate macrophage integrin αvβ5-mediated efferocytosis. This mechanism drives macrophage polarization toward regenerative M2 phenotypes, ensures adaptability to the adult environment, and reprograms mesenchymal stem cells to orchestrate developmental recapitulation. Consequently, pDev-dECM not only enabled in situ hierarchical regeneration of the periodontal complex but also facilitated cross-organ hierarchical regeneration in skin and muscle defect models. These findings demonstrate that pDev-dECM exerts spatiotemporal control over developmental recapitulation, establishing a universal biomaterial paradigm for multiscale tissue reconfiguration.