Advanced Biomaterial Delivery of Hypoxia‐Conditioned Extracellular Vesicles (EVs) as a Therapeutic Platform for Traumatic Brain Injury

Abstract Traumatic Brain Injury (TBI) is a common and debilitating injury, causing long‐lasting neurological deficits. Current therapeies for recovery remain inadequate, undersing the urgent need for innovative interventions. In this study, a novel therapeutic approach is introduced that delivers extracellular vesicles (EVs) derived from human‐induced pluripotent stem cell‐derived neural progenitor cells (hiPSC‐NPCs) with a gelatin‐based injectable bioorthogonal hydrogel (BIOGEL). The hiPSC‐NPCs are conditioned with deferoxamine (DFO) to simulate hypoxia, resulting in EVs enriched with neurotrophic and angiogenic factors critical for neural repair. The biomimetic mechanical properties of BIOGEL, similar to those of native brain tissue, contribute to sustained EV delivery and promote neural regeneration. BIOGEL with hypoxia‐conditioned EVs showed significant tissue regeneration in vivo using a rat model of TBI. Our nanomaterial platform reduced cortical lesions, improved neurological and motor recovery, enhanced hippocampal neurogenesis and myelination, and reduced neuroinflammation, demonstrating strong therapeutic potential for neural repair. In summary, this study demonstrated proof‐of‐concept for a multifaceted therapeutic platform that simultaneously targets key pathological features of TBI, providing a scalable and clinically translatable approach to effective neural tissue regeneration. The synergistic combination of hypoxia‐conditioned EVs and biomaterial delivery offers a promising strategy for advancing regenerative medicine techniques for neural repair.