Free radical as a double-edged sword in disease: Deriving strategic opportunities for nanotherapeutics

Free radicals, usually containing one or more unpaired electrons, are extremely unstable and highly reactive with other biological molecules. Recently, there has been increasing interest and substantial progress in exploring the double-edged roles of free radicals in biological systems. Particularly, nanotherapeutics based on free radical regulation have emerged as a new treatment modality against various diseases. Herein we provide a state-of-the-art review on free radicals as a double-edged sword in various disease treatments, which derives new opportunities for future nanotherapeutics. In this review, the major sources, types, and physiological functions of free radicals are firstly introduced. A specific focus is placed on the emergence of free radical generation-based nanotherapeutic approaches, including photodynamic therapy (PDT), sonodynamic therapy (SDT), radiation therapy (RT), chemodynamic therapy (CDT), ferroptosis therapy, and other nanotherapeutics involving free radical generation strategies. Subsequently, free radical depletion-based nanotherapeutics for alleviating molecular damage and related diseases are presented with emphasis on the treatment of inflammatory diseases, neurodegenerative disorders, cardiovascular and cerebrovascular diseases, acute kidney/liver injury, diabetes and diabetic complications, tumorigenesis and so on. Finally, some ongoing challenges and insightful perspectives of the currently developed nanotherapeutics based on regulating free radicals in biomedicine are discussed. We believe that this review would appeal to the researchers from interdisciplinarity fields of nanoscience, chemistry, biology, material science, pharmaceutical science, as well as clinical medicine to push the development of related nanotherapeutic technologies.