Hemostatic, Antimicrobial, and Thixotropic Hydrogels Based on Natural Silk Nanofibril/Halloysite Nanotube/Extracellular Vesicle Hybrids

Abstract Thixotropic silk fibroin hydrogels have demonstrated great potential in biomedical applications, yet additional properties need to be integrated to meet specific clinical demands, such as hemostatic and antimicrobial abilities for wound dressing. Herein, tetracycline hydrochloride (TCH)‐loaded halloysite nanotubes (HNTs) are incorporated with silk nanofibrils (SNFs) to prepare a SNF/TCH@HNTs hybrid hydrogel. The incorporation of TCH@HNTs into the SNF hydrogel not only preserved its excellent thixotropic properties but also endowed it with considerable hemostatic and antimicrobial capabilities. The outstanding coagulation effect of HNTs made the hydrogels exhibit significant hemostatic effects in both mouse tail amputation and liver laceration model. Furthermore, the hierarchical structure of SNF/TCH@HNTs hydrogel effectively reduced the burst release of TCH, enabling the hydrogel to maintain good antimicrobial efficacy for one week. In addition, given the importance of proliferation and remodeling/maturation phases in the wound healing process, extracellular vesicles derived from dental pulp stem cells (D‐EVs), known for their immense potential in promoting angiogenesis and collagen formation, are further incorporated into SNF/TCH@HNTs hydrogel. Ultimately, the SNF/TCH@HNTs/D‐EVs hydrogel showed a significant enhancement in wound healing for full‐thickness skin wounds infected with Staphylococcus aureus in mice. Therefore, such a multifunctional silk‐based thixotropic hydrogel holds promising potential for application in biomedical fields.