A multifunctional injectable nanocomposite hydrogel for precision keloid therapy via ECM remodeling and local pruritus relief

Keloids are refractory fibroproliferative disorders. Their treatment faces multiple clinical challenges, including the coexistence of multiple pathological mechanisms, low drug bioavailability, and keloid-related pruritus. This study developed an UV-responsive cross-linked hydrogel (FZRL) using lipoic acid-grafted chitosan (LACS) as the matrix. The hydrogel encapsulates ZIF-8 nanoparticles loaded with 5-fluorouracil (5Fu, denoted as 5Fu@ZIF-8) and the local anesthetic ropivacaine. Before injection, the hydrogel exists as a liquid precursor. It can be precisely delivered to the area around keloids. Under mild UV irradiation, it rapidly cross-links into a stable hydrogel. This enables long-term local retention of 5Fu and ropivacaine, preventing premature drug leakage. In the weakly acidic microenvironment of keloids, FZRL hydrogel degrades specifically and releases 5Fu and ropivacaine on demand. A nude mouse keloid model with subcutaneous inoculation of human keloid fibroblasts (KFs) showed that FZRL hydrogel regulates the TGF-β/Smad pathway. It inhibits KFs proliferation and abnormal angiogenesis, modifies the extracellular matrix structure, and remodels the keloid microenvironment. After treatment, the average keloid volume was reduced by 54.7 ± 12.1%. At the same time, it significantly relieved itching-related scratching and irritable behaviors. In conclusion, FZRL hydrogel has dual delivery properties, including UV-responsive gelation and acid-responsive drug release. It synergistically achieves multi-target anti-keloid effects, as well as pruritus relief and analgesia. It provides a new minimally invasive treatment strategy for refractory keloids and has potential clinical translation value.