<p>Incorporation of ROS-Responsive Substance P-Loaded Zeolite Imidazolate Framework-8 Nanoparticles into a Ca<sup>2+</sup>-Cross-Linked Alginate/Pectin Hydrogel for Wound Dressing Applications</p>

Purpose: Wound healing, especially of extensive full-thickness wounds, is one of the most difficult problems in clinical studies. In this study, we prepared a novel substance P (SP)-delivery system using zeolite imidazolate framework-8 (ZIF-8) nanoparticles. Methods: We synthesized ZIF-8 nanoparticles using a modified biomimetic mineralization method. We then coated SP-loaded ZIF-8 nanoparticles ( [email protected] ) with polyethylene glycol-thioketal (PEG-TK) to fabricate [email protected] nanoparticles, and encapsulated them in injectable hydrogel composed of sodium alginate and pectin and cross-linked using calcium chloride. The final hydrogel wound dressing containing [email protected] nanoparticles was called [email protected] @CA. Results: The fabricated ZIF-8 nanoparticles had high SP-loading efficiency. SP-release assay showed that the [email protected] nanoparticles maintained drug activity and showed responsive release under stimulation by reactive oxygen species. The [email protected] nanoparticles promoted proliferation of human dermal fibroblasts, up-regulated expression levels of inflammation-related genes in macrophages, and exhibited favorable cytocompatibility in vitro. Full-thickness excision wound models in vivo confirmed that [email protected] @CA dressings had excellent wound-healing efficacy by promoting an early inflammatory response and subsequent M2 macrophage polarization in the wound-healing process. Conclusion: In conclusion, these findings indicated that [email protected] @CA dressings might be useful for wound dressing applications in the clinic. Keywords: substance P, metal-organic framework, nanoparticles, hydrogel, wound healing