Synergistic Wound Healing: Unraveling the Multi-Target Effects of Traditional Chinese Medicine and Its Biomaterials on Chronic Wound Pathways

Jiayu Shen,1,2,* Zhuo Tong,1,2,* Bing Han,1,2 Ziyin Zhang,1,2 Zudan Xian,1,2 Yao Yuan,1,2 Xinliang Duan,1,2 Sichen Han,1,2 Peng Liu,2,3 Zilin Wang1,2 1Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China; 2Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, People’s Republic of China; 3VIP Department, Hospital of Stomatology, Jilin University, Changchun, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zilin Wang, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China, Tel +18744014751, Email [email protected] Peng Liu, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China, Tel +18744014751, Email [email protected]: Chronic wounds, including diabetic ulcers (DUs), radiation-induced ulcers, and burns, present significant clinical challenges due to their distinct pathological mechanisms, necessitating tailored therapeutic strategies. Diabetic ulcers, characterized by impaired angiogenesis, persistent inflammation, and hyperglycemia, require dual modulation of inflammatory (NF-κB) and pro-repair (PI3K/Akt, Nrf2) pathways. Radiation ulcers involve DNA damage, NLRP3-driven inflammation, and TGF-β/Smad-mediated fibrosis, while burns trigger acute inflammation via DAMPs/PAMPs-TLR/NLR activation. Traditional Chinese medicine (TCM) and its bioactive components, such as Scutellaria baicalensis, curcumin, and Panax notoginseng, exhibit multi-target therapeutic effects by regulating oxidative stress, inflammation, angiogenesis, and extracellular matrix remodeling through key pathways, including Nrf2/ARE, MAPK, NF-κB, PI3K/Akt, HIF-1α/VEGF, Wnt/β-catenin, and TGF-β/Smad. Emerging supramolecular self-assembled biomaterials—nanofibrous scaffolds, hydrogels, and microneedles—address the hydrophobicity and low bioavailability of natural plant-derived macromolecules (NPHMs), enabling spatiotemporally controlled drug delivery. Innovative formulations, such as curcumin-loaded hydrogels and exosome-based systems, enhance antioxidant, anti-inflammatory, and pro-angiogenic activities, accelerating wound closure. Despite progress, challenges remain in optimizing multifunctional co-assembly systems, elucidating NPHM self-assembly mechanisms, and developing smart biomaterials responsive to dynamic wound microenvironments. Future research should focus on clinical translation by improving material stability, refining stimulus-responsive release systems, and integrating interdisciplinary insights from herbal medicine, nanotechnology, and regenerative biology. This review systematically summarizes the mechanistic roles of TCM in wound healing, highlights advancements in bioactive material design, and outlines future directions to bridge traditional knowledge with modern therapeutic innovations, offering a scientific foundation for advancing chronic wound management.Keywords: chronic wounds, traditional Chinese medicine, biomaterials, signaling pathways, wound healing