Black Phosphorus-Loaded Gelatin Methacryloyl Hydrogels Enhance Angiogenesis via Activation of the PEAK1–MAPK Pathway

Repair and regeneration of oral and maxillofacial tissue defects remain significant challenges, mainly due to the limitations of existing treatment approaches. Conventional methods such as transplantation, tissue scaffolds, growth factors, and stem cell therapies often face obstacles, including donor shortages, insufficient vascularization, and safety concerns. There is an urgent need for innovative therapeutic strategies to effectively promote vascular regeneration while minimizing complications. Black phosphorus nanosheets (BPNSs) and hydrogels present significant advantages and broad application potential as tissue regeneration carriers due to their biocompatibility, degradability, and controlled drug release properties. By combining various characterization techniques and detection methods, we conducted a thorough analysis of BPNSs and gelatin methacryloyl (GelMA) scaffolds loaded with BPNSs (BP-GelMA). The results indicate that this study successfully prepared BPNSs with uniform size, good dispersion, and intact structure. Moreover, the BP-GelMA composite demonstrated excellent swelling behavior and structural stability while effectively enabling the controlled release of BPNSs. This study investigated the angiogenic effects of BP-GelMA at concentrations of 0, 12.5, and 25.0 μg/mL. <i>In vitro</i> experiments showed that BP-GelMA significantly enhanced endothelial cell proliferation, migration, and tube formation. <i>In vivo</i> results demonstrated that 12.5 μg/mL and 25.0 μg/mL BP-GelMA did not induce significant developmental toxicity in zebrafish and effectively promoted neovascularization. RNA-Seq analysis revealed that BP-GelMA activates angiogenesis-related biological processes. Mechanistic studies identified PEAK1 as a central regulator, driving vascular formation through activation of the MAPK signaling pathway. These findings highlight the potential of BP-GelMA as a therapeutic strategy for promoting angiogenesis and underscore the importance of optimizing BP-GelMA concentrations to achieve maximum therapeutic efficacy and safety in clinical applications.