Nano-radiosensitizers targeting tumor radioresistance: mechanisms, rational design, and clinical prospects

Abstract

Radiotherapy is one of the most widely used treatment modalities for cancer, but its therapeutic efficacy is often limited by inherent tumor radioresistance and radiation-induced damage to surrounding normal tissues. Nano-radiosensitizers have emerged as a versatile platform to improve therapeutic outcomes relying on selectively augmenting the sensitivity of malignant cells to ionizing radiation. Driven by a deep understanding of radioresistance mechanisms, recent advances have enabled the engineering of diverse nano-radiosensitizers that act through distinct pathways, including inhibition DNA damage repair pathways, alleviation tumor hypoxia, regulation of the tumor immune microenvironment, modulation of cell cycle progression, and enhancement of reactive oxygen species production. This review systematically categorized current frontier studies of nano-radiosensitizers for preclinical external radiotherapy based on the core radiosensitizing mechanisms, critically assessed the advantages and limitations of each strategy and highlighted representative examples from recent preclinical studies. The article also discusses the key challenges that hinder clinical application and outlines the future development directions to guide the development of next-generation nano-radiosensitizers with higher efficacy and safety.