Radiotherapy remains one of the main pillars of cancer treatment and is used in more than half of all oncological patients. Despite continuous technological improvements, ionizing radiation inevitably causes damage to surrounding healthy tissues, leading to acute and chronic complications affecting multiple organs, including the skin, mucosa, heart, lungs, bones and gastrointestinal tract. Radiation-induced injuries significantly impair patients’ quality of life, limit therapeutic doses, and represent a major unmet clinical challenge. Hydrogels have emerged as promising biomaterials for managing radiation-induced damage due to their high content of water, tunable mechanics, and ability to mimic the extracellular matrix. Recent innovations have introduced functional systems, including stimuli-responsive, injectable, and bioactive hydrogels, capable of delivering antioxidants, growth factors, or living cells. Unlike traditional material-based reviews, this work proposes a novel classification framework based on the hydrogel’s mechanism of action within the pathophysiology of radiation injury. We evaluate how specific designs, such as ROS-scavenging matrices, barrier-forming injectable shields, and bioactive delivery vehicles, address distinct phases of inflammation and fibrosis. By providing a comprehensive overview of radiation-induced injuries across different organs, this review summarizes current hydrogel-based strategies for both prevention and therapy. We highlight the potential of these mechanistically aligned systems to protect healthy tissues, suppress chronic inflammation, and promote effective tissue regeneration.

Radiotherapy remains one of the main pillars of cancer treatment and is used in more than half of all oncological patients. Despite continuous technological improvements, ionizing radiation inevitably causes damage to surrounding healthy tissues, leading to acute and chronic complications affecting multiple organs, including the skin, mucosa, heart, lungs, and gastrointestinal tract. Radiation-induced injuries significantly impair patients’ quality of life, limit therapeutic doses, and represent a major unmet clinical challenge. Hydrogels have emerged as a highly promising class of biomaterials for the management of radiation-associated tissue damage due to their high water content, tunable mechanical properties, biocompatibility, and ability to mimic the extracellular matrix. In recent years, significant advances have been made in the design of functional hydrogels, including stimuli-responsive, injectable, adhesive, and bioactive systems capable of delivering drugs, growth factors, antioxidants, or living cells. This review provides a comprehensive overview of radiation-induced injuries in different organs and summarizes current strategies employing hydrogel-based systems for their treatment. We discuss both therapeutic and preventive applications of hydrogels, highlighting their potential to protect healthy tissues, reduce inflammation and fibrosis, and promote tissue regeneration.