Abstract

Uncontrollable hemorrhage remains a leading cause of trauma-related mortality, where existing hemostats often fail to balance mechanical robustness and biodegradability, hindering integrated hemostasis and tissue regeneration. Here, we break this paradox with a bio-inspired programmable assembly strategy that mimics the hierarchical self-assembly of natural proteins. By orchestrating sequential hydrogen-bond-driven pre-organization, covalent locking, and freeze-drying, we construct a multifunctional cryogel (PUS-SIS@TA) from decellularized small intestinal submucosa (SIS), disulfide-containing polyurethane, and tannic acid. It integrates exceptional fluid absorption (>40 × its weight in blood), shape memory (<2 s) and unique blood-triggered mechanical reinforcement (11.5-fold increase). Upon contact with blood, platelets and erythrocytes were engaged, amplifying physiological coagulation while simultaneously enhancing clot stability. In lethal non-compressible hepatic hemorrhage models in rabbits and beagles, the cryogel achieves rapid hemostasis, outperforming commercial sponges. Subsequently, its disulfide bonds enable controlled degradation, allowing the material to seamlessly transition from a hemostat to a bioactive scaffold. This transition releases SIS-derived cues that orchestrate angiogenesis, biliary reconstruction, and functional liver regeneration. By learning from how nature builds rather than what it builds, this work offers a promising solution for integrated hemostasis management and tissue regeneration, and also provides a universal perspective for the design of novel biomaterials.