In situ forming AIEgen-alginate hydrogel for remodeling tumor microenvironment to boost FLASH immunoradiotherapy

FLASH radiotherapy, which involves the delivery of an ultra-high radiation dose rate exceeding 40 Gy/s, has emerged as a promising tumor ablation strategy. While this approach generally spares normal tissues, the incomplete killing of tumors may sometimes lead to recurrence due to the immunosuppressive tumor microenvironment (TME). Herein, an aggregation-induced-emission luminogen (AIEgen)-alginate hydrogel was used to sensitize colon cancer via photodynamic therapy (PDT). Flower-like calcium carbonate nanoparticles, doped with an AIEgen termed CQu, were designed and applied as a cocktail with sodium alginate. When exposed to the acidic TME, Ca²⁺ is released from this structure, resulting in sodium alginate termed FA forming a hydrogel in situ within the TME. This hydrogel also captures high concentrations of CQu in the local TME. Under laser irradiation, the CQu can generate sustained reactive oxygen species (ROS) production, thereby facilitating Ca²⁺ influx and causing mitochondrial damage. Through a single injection of established FA hydrogel, followed by PDT and FLASH radiotherapy, immunogenic tumor cell death was induced which promoted antitumor immunity, thereby protecting against tumor recurrence while realizing abscopal effect. The results highlight the potential to improve the sensitivity of tumor cells to FLASH radiotherapy through sustained ROS production and Ca²⁺ overload, thereby yielding optimal immunotherapy outcomes.