Radiation-induced skin injury (RISI) is a common complication of tumor radiotherapy. Its pathogenesis is closely associated with radiation-induced oxidative stress and persistent inflammatory responses, yet effective prevention and treatment strategies remain lacking. Shikonin, the core active component of the traditional Chinese medicinal herb Lithospermum erythrorhizon, exhibits significant antioxidant and anti-inflammatory activities. However, its clinical application is limited by chemical instability, hydrophobicity, and low bioavailability. Exosomes (Exos), as natural drug delivery systems, can enhance drug stability and delivery efficiency, while the SPACE peptide significantly improves transdermal drug absorption. This study innovatively combines SPACE peptide-modified exosomes with shikonin to construct a transdermal delivery system (SK@SP-Exos). Furthermore, the system is encapsulated in sodium alginate hydrogel to prolong local drug retention, aiming to overcome skin barrier limitations and enhance therapeutic efficacy for RISI.
The study successfully prepared SPACE peptide-modified shikonin-loaded exosomes (SK@SP-Exos) with uniform particle size, stable structure, and a shikonin loading efficiency of 23%. In vitro experiments demonstrated that SK@SP-Exos exhibited superior skin permeability and cellular uptake capacity. It significantly inhibited radiation-induced reactive oxygen species (ROS) generation, suppressed lipopolysaccharide (LPS)-stimulated expression of pro-inflammatory factors (e.g., IL-6, TNF-α), and promoted the proliferation of skin fibroblasts. In the RISI mouse model, SK@SP-Exos-loaded hydrogel markedly accelerated skin injury repair by inhibiting macrophage infiltration, alleviating inflammatory responses, promoting angiogenesis and collagen deposition, with no apparent systemic toxicity observed.
The SK@SP-Exos composite hydrogel system developed in this study integrates efficient transdermal delivery capability with excellent biocompatibility, addressing critical bottlenecks in the clinical application of shikonin. Through synergistic multi-mechanistic actions—including antioxidant, anti-inflammatory, pro-proliferative, and pro-angiogenic effects, it significantly enhances RISI repair. This system provides a safe and effective novel therapeutic strategy for radiation-induced skin injury, demonstrating promising clinical translation prospects.