Natural Small Molecule Self‐Assembled Hydrogel Inhibited Colorectal Cancer Progression by Regulating Cuproptosis and PANoptosis

Abstract Copper‐mediated and mitochondrion‐dependent cuproptosis is an emerging paradigm of programmed cell death, gathering significant attention for its potential application in cancer therapy. A natural small molecular‐free injectable hydrogel (Lyc@GA‐Cu Gel) is prepared by Cu 2+ mediated self‐assembly of glycyrrhizic acid (GA) and lycorine (Lyc), primarily driven by coordination and hydrogen bonding. In vitro and in vivo results show that Lyc@GA‐Cu Gel can act as copper ionophores to induce the occurrence of cuproptosis in colorectal cancer cells, and further produce massive reactive oxygen species (ROS), amplifying oxidative stress reaction, ultimately triggering PANoptosis (apoptosis, pyroptosis, necroptosis). Compared to free Lyc, Lyc@GA‐Cu Gel exhibits superior antitumor efficacy and biocompatibility, with enhanced tumor accumulation and sustained release capabilities. Notably, Lyc@GA‐Cu Gel components are derived from clinical preparations without any excipients. Moreover, the preparation process is straightforward, economic, and environmental, presenting a promising prospect of clinical transformation and industrial production.