Essential trace elements (ETEs) are crucial nutrients in maintaining the immune function of the body. Designing nanomedicines based on ETEs has become an emerging strategy for enhancing immunotherapy by utilizing the metabolism of constituent ETEs and their immunomodulatory functions. However, their medical applications are challenged by the dosage-dependent balance between therapeutic necessity and toxicity. The narrow safety zones of ETEs pose great challenges for high efficacy without exceeding strict safety thresholds. Nanomedicinal strategies based on multiple ETEs hold promising potentials for exerting safe and effective immunomodulation functions of ETEs with an expanded therapeutic window. Herein, ultrasmall ZnS/Se/BSA nanoclusters (ZSB NCs) were synthesized via a biomineralization approach, acting as a synergetic lymph nodes (LNs)-targeting nanoplatform integrating the immunomodulatory effects of ETEs (Zn and Se) and the advantages of albumins for cancer immunotherapy. ZSB NCs could remarkably target LNs after subcutaneous injection, where the released zinc ions and transformed selenoproteins stimulated the cyclic guanosine monophosphate-adenosine monophosphate synthase-interferon gene (cGAS-STING) pathway. Subsequently, ZSB NCs effectively induced the activation and maturation of dendritic cells (DCs) and activated T cells to secrete inflammatory factors for enhancing immunomodulatory effects. The cancer immunotherapy efficacy and biosafety of ZSB NCs were validated in a orthotopic breast cancer model, where tumor growth was significantly suppressed. Our findings indicate that ZSB NCs can act as a promising candidate for improved synergetic cancer immunotherapy.
