Radiodermatitis, one of the most prevalent side effects of cancer radiotherapy, is characterized by cellular oxidative stress, mitochondrial damage, and inflammatory responses. In this study, we isolated extracellular vesicles (EVs) from the natural microalgae Spirulina platensis (SP) and engineered them by loading astaxanthin (AST) into SP-EVs, resulting in the formation of SP-EVs@AST. This engineered system significantly enhanced the solubility and stability of AST while preserving the structural integrity and biological activity of SP-EVs, thereby enabling the complementary and synergistic effects of AST and SP-EVs. SP-EVs@AST demonstrated protective effects against radiation-induced cellular damage by alleviating oxidative stress, restoring mitochondrial function, and reducing inflammatory responses. To optimize topical administration, SP-EVs@AST were incorporated into a self-assembled hydrogel composed of aldehyde-functionalized hyaluronic acid (HA-CHO) and carboxymethyl chitosan (CMCS), forming a skin radiation protection dressing (SP-EVs@AST gel). This dressing effectively preserved the activity of SP-EVs@AST, facilitated its sustained release, protected the skin from progressive radiation-induced injury, and exhibited long-term biological safety. This system demonstrates the potential of engineered microalgal EVs as carriers for poorly soluble drugs, offering a promising strategy to expand their application as a targeted drug delivery platform in biomedical fields.
