Porphyrin-Engineered ¹²⁵I-Nanoseeds as a Prototype for Immunogenic Brachytherapy

Internal radiotherapy holds a greater potential than external radiotherapy for precisely destroying tumors and minimizing side effects. ¹²⁵I seeds are routinely used as radioactive sources in clinical brachytherapy for patients with various types of cancers. However, ¹²⁵I seeds are losing ground to flashier cancer therapies, mainly due to their limited therapeutic efficacy, uneven dose distribution, and negligible antitumor immune response. Here, we present porphyrin-engineered ¹²⁵I-nanoseeds as a prototype for immunogenic brachytherapy. ¹²⁵I-nanoseeds were rationally designed as a core-shell structure, in which Au@Ag cores enhance the energy deposition of photons to produce more ·OH, while porphyrin shells transfer the energy of Auger electrons to generate ¹O₂. Benefiting from improving energy utilization efficiency, ¹²⁵I-nanoseeds can efficiently produce ·OH and ¹O₂ in tumors, enhancing antitumor efficacy and inducing immunogenic cell death in both murine tumor models and human tumor tissues. When combined with checkpoint blockade immunotherapy, ¹²⁵I-nanoseeds elicit a systemic immune response in tumor-bearing mice, inhibiting both distant and metastatic tumors. This work demonstrates that porphyrin-engineered ¹²⁵I-nanoseeds can synergize brachytherapy and dynamic therapy, resulting in enhanced antitumor efficacy and antitumor immune response compared to those of clinical ¹²⁵I seeds, which is expected to improve the applied prospect of clinical brachytherapy.