Radiotherapy (RT) is the cornerstone of cancer treatment, but its clinical efficacy is frequently hampered by radiation-induced damage to normal tissues and the radioresistance of tumors. As a natural biopolymer, melanin demonstrates the potential for a bidirectional role in radioprotection and radiosensitization due to its unique physicochemical properties. This review systematically analyzes the bidirectional roles of melanin and engineered melanin nanomaterials (EMNMs) in tumor RT. Under physiological conditions, melanin predominantly functions as a radioprotector by absorbing radiation, scavenging reactive oxygen species (ROS), chelating metal ions, and regulating redox states. Conversely, in pigmented tumors such as melanoma, melanin overproduction leads to RT resistance. This resistance is driven by mechanisms including the “ROS sponge” effect, hypoxia induction, metabolic reprogramming, and interference with immune activation. To circumvent RT resistance, research strategies have expanded from inhibiting melanin synthesis to its functional engineering. Through synthetic biology and nanotechnology, melanin—especially melanin-like substances such as polydopamine (PDA)—can be atomically doped, structurally designed, and functionally loaded to construct multifunctional nanoplatforms. Consequently, these EMNMs can convert RT resistance into RT sensitization by enhancing physical energy deposition, catalyzing chemical reactions, regulating the hypoxic tumor microenvironment (TME), and synergizing with immunotherapy (IT). Furthermore, their utility can be extended to broad-spectrum sensitization applications in non-pigmented tumors. Melanin and EMNMs are emerging as highly promising platforms for realizing “bidirectional precision RT” (i.e., targeted tumor eradication concurrent with precise normal tissue preservation) and broad-spectrum RT sensitization. Future challenges lie in developing intelligent responsive materials and systematically evaluating their long-term biosafety, ultimately driving the clinical translation of personalized RT sensitization strategies.
Chen et al. (Thu,) studied this question.