Polyphenols and Flavonoids in Wound Healing: Molecular Mechanisms, Therapeutic Potential, and Advanced Delivery Strategies

Wound healing is a complex and tightly regulated biological process involving the sequential phases of hemostasis, inflammation, proliferation, and tissue remodeling. Persistent oxidative stress and chronic inflammation can impair these processes, resulting in delayed healing and the development of chronic wounds. Polyphenols and flavonoids, a diverse class of plant-derived bioactive compounds, have attracted considerable interest because of their antioxidant, anti-inflammatory, antimicrobial, and tissue-regenerative properties. Their therapeutic effects are mediated through multiple molecular mechanisms, including reactive oxygen species scavenging, activation of the Nrf2 antioxidant pathway, inhibition of nuclear factor-kappa B signaling, modulation of inflammatory cytokine production, promotion of vascular endothelial growth factor-mediated angiogenesis, and enhancement of extracellular matrix remodeling and collagen deposition. Representative phytochemicals, including curcumin, quercetin, resveratrol, epigallocatechin gallate, kaempferol, and rutin, have demonstrated significant wound-healing potential in both in vitro and in vivo studies. Recent advances in drug delivery systems, such as nanoparticles, hydrogels, nanofibers, and bioengineered scaffolds, have further enhanced the stability, bioavailability, and therapeutic efficacy of these compounds. Despite encouraging pre-clinical and emerging clinical evidence, challenges related to poor bioavailability, inadequate standardization, and limited clinical translation continue to hinder their broader therapeutic application. This review provides a comprehensive overview of the molecular mechanisms, therapeutic potential, advanced delivery strategies, present evidence, existing limitations, and prospects of polyphenols and flavonoids in wound healing and regenerative medicine.