Exosome-loaded nanoradiosensitizers in radiotherapy for preventing post-irradiation tumor recurrence: mechanisms, preclinical evidence, and translational challenges

Radiotherapy remains a cornerstone in cancer treatment, yet its therapeutic efficacy is often limited by radioresistance, tumor heterogeneity, and recurrence post-irradiation. Nanotechnology has emerged as a promising avenue to enhance radiosensitization, improve tumor selectivity, and reduce off-target toxicity. Among these, exosome-loaded nanoradiosensitizers represent an innovative strategy, leveraging the natural biocompatibility, tumor-homing ability, and immunomodulatory properties of exosomes to deliver radiosensitizing agents with precision. This review examines the design principles, fabrication strategies, and functional mechanisms of exosome-based nanoradiosensitizers, highlighting how they enhance DNA damage, modulate the tumor microenvironment, and overcome intrinsic and acquired radioresistance. We discuss the molecular mechanisms underlying radiosensitization, including reactive oxygen species (ROS) amplification, cell-cycle modulation, hypoxia alleviation, and immune system engagement. Furthermore, we explore in vitro and in vivo preclinical evidence demonstrating the efficacy of these systems in reducing tumor recurrence post-irradiation. Challenges such as scalable exosome production, cargo loading efficiency, targeted delivery, and regulatory considerations are critically evaluated. Finally, the review outlines translational perspectives, potential combinatorial therapies, and key considerations for clinical trial design. By integrating insights from nanomedicine, radiobiology, and exosome biology, this review aims to provide a comprehensive framework for the development of next-generation exosome-based nanoradiosensitizers, ultimately enhancing radiotherapy outcomes and minimizing tumor relapse in resistant cancers.