Thermal‐Triggered Polymerizable Hydrogels with Localized Hyperthermia for Shrinkage‐Driven Starvation Therapy

Abstract Despite starvation therapy, a potential approach to suppress tumor angiogenesis via blood‐blocking and nutrient deprivation, holds therapeutic potential, its efficacy remains undesired. Herein, a thermal‐sensitive dual‐modality strategy is developed to construct injectable interpenetrating polymer network (IPN) hydrogels. This approach integrates vascular compression through deformation‐driven shrinkage and localized hyperthermia for starvation therapy. IPN hydrogels comprise two sequentially injected components: a thermal‐triggered polymerizable moiety (“A glue”) and a hyperthermia moiety (“B glue”). By manipulating the lower critical solution temperature via adjustment of N‐isopropylacrylamide ratios, the disrupted hydrogen bond of A glue precursor causes substantial heat release to reactivated free radicals, enabling in situ polymerization at physiological temperatures. Subsequent injection of B glue's precursor generates localized heat through exothermic radical polymerization. Concurrently, extravascular gelation shrinkage induces internal stress, mechanically compressing blood vessels. In vivo antitumor results demonstrated that IPN hydrogels has a capability of diminishing vascular density, inducing hypoxia and apoptosis, ultimately achieving effective tumor suppression. Taken together, these findings will provide a novel design principle for developing chemotherapy‐ and phototherapy‐free starvation therapy.