Tailoring the therapeutic potential of stem cell spheroid-derived decellularized ECM through post-decellularization BDNF incorporation to enhance brain repair.

Decellularized extracellular matrix (dECM) from tissues has significant therapeutic potential but is limited by its rigid molecular composition and reliance on post-decellularization modifications to tailor its functionality. Harsh decellularization processes often result in substantial glycosaminoglycan (GAG) loss, impairing natural growth factor incorporation and necessitating chemical modifications that complicate processing and limit clinical translation. To address these challenges, we developed mesenchymal stem cell (MSC) spheroid-derived three-dimensional (3D) dECM using gentle decellularization techniques. This study demonstrated a crucial advancement-the retention of endogenous GAGs-enabling direct growth factor incorporation without chemical agents. As a proof-of-concept, brain-derived neurotrophic factor (BDNF) was incorporated into the 3D dECM to enhance its therapeutic potential for brain repair. In vitro, BDNF-loaded 3D dECM enabled sustained growth factor release, significantly enhancing the proneuritogenic, neuroprotective, and proangiogenic effects. In a mouse model of traumatic brain injury, the implantation of BDNF-loaded 3D dECM significantly enhanced motor function and facilitated brain repair. These findings highlight the adaptability of MSC spheroid-derived 3D dECM for tissue-specific customization through straightforward and translatable growth factor incorporation, demonstrating its potential as a pro-regenerative biomaterial for advancing regenerative medicine applications.