Injectable acid-labile thermosensitive magnetic hydrogel with responsive drug release for bridging liver transplantation in hepatocellular carcinoma.

Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(N-isopropylacrylamide)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.