<p>The effective healing of skin wounds, particularly chronic wounds such as diabetic ulcers, remains a major clinical challenge. The abundance of research on natural compounds has, paradoxically, created a new challenge: the absence of a comparative framework to guide their selection for specific wound types and mechanisms of action. This review aims to bridge this gap by providing a structured assessment of prominent natural materials and their nano-formulations, focusing on their ability to regulate key signaling pathways involved in wound repair. We conducted a comprehensive narrative review of natural compounds and their nano-based formulations, specifically collagen, chitosan, curcumin, dendrimers, graphene, and essential oils used in wound healing. Evidence demonstrates that these materials synergistically accelerate all phases of wound healing (hemostasis, inflammation, proliferation, and remodeling) by modulating critical signaling pathways. Key findings highlight that curcumin attenuates inflammation and oxidative stress via inhibition of the NF-κB pathway and ROS scavenging; collagen and chitosan enhance extracellular matrix (ECM) deposition and angiogenesis through activation of TGF-β and VEGF pathways; and nano-formulations significantly improve the stability, bioavailability, and targeted delivery of natural agents, thereby amplifying their antioxidant, antimicrobial, and pro-angiogenic effects. Future efforts should focus on well-designed clinical trials, long-term toxicity assessments, and scalable production strategies to enable clinical translation of these promising biomaterials.</p> Graphical abstract <p></p>