Fuel to fire: developmental niche-empowered ApoEVs unlock adult hierarchical tissue regenerative potential via mitochondrial complex I-driven developmental metabolic profile

Organ defects involving hierarchical tissue structures remain a major challenge due to limited regenerative capacity in adulthood. To break this bottleneck, regenerative medicine is undergoing a paradigm shift from simulating the healing process of mature organs to reactivating re-development potential, namely developmental engineering strategy. In this study, we propose a novel paradigm based on developmental niche-empowered stem cell-derived apoptotic extracellular vesicles (DevNiche-ApoEVs), which integrates cues from both parental stem cells and their environmental niches. Using the periodontium as a classical hierarchical model, we identified developmental M2-phenotype macrophages (DevM2φ) as a key niche component that induces a developmental metabolic profile in stem cells, characterized by enhanced energy metabolism, mitochondrial homeostasis, and dominance of oxidative phosphorylation. We subsequently empowered ApoEVs with DevM2φ-mediated developmental niche to generate DevNiche-ApoEVs capable of delivering mitochondrial complex I and recapitulating the developmental metabolic profile. In vitro studies confirmed DevNiche-ApoEVs reactivated the developmental potential of adult periodontal ligament cells (PDLCs), while complex I inhibition abrogated this effect. Consistently, DevNiche-ApoEVs promoted re-development-based hierarchical periodontal regeneration by recapitulating critical developmental events in vivo. This study highlights the pivotal role of the developmental niche in hierarchical tissue regeneration and provides a promising DevNiche-ApoEVs-focused developmental engineering strategy, which offers both a solid theoretical foundation and an effective translational solution to overcome the longstanding bottleneck in adult tissue regeneration.