Hierarchically Aligned HNTs-Based Composite Foam with Immunomodulatory Activity for Diabetic Wound Healing.

Diabetic wound healing remains a significant clinical challenge due to persistent inflammatory and impaired tissue repair. Herein, a hierarchically aligned composite foam based on halloysite nanotubes (HNTs) was rationally designed using a cooling-assisted fabrication to achieve integrated structural alignment and multifunctional regulation. Building upon our previous work demonstrating temperature management and hemostatic performance in acute wounds, this study systematically investigates the applicability of the foam in diabetic wound healing and elucidates the associated biological responses. The findings suggested that this hierarchically aligned foam material accelerated wound healing in diabetic rats, accompanied by reduced inflammatory marker expression, enhanced angiogenesis-related responses, and increased collagen deposition. In vitro studies revealed that the foam material facilitated macrophage migration and polarization toward the reparative phenotype. Transcriptomic sequencing and protein assays revealed that the foam-induced macrophage response was associated with the activation of PI3K/AKT signaling in vitro. Moreover, PI3K inhibition attenuated the anti-inflammatory and prohealing effects observed in RAW264.7 macrophages, supporting the involvement of this pathway in vitro macrophage response. Overall, this work suggests that rational material design with hierarchical alignment may modulate immune responses and promote diabetic wound repair, highlighting the potential of HNTs-based composite foams for advanced wound management applications.