Bioinspired Hf-based metal-organic framework radiosensitizer for nitric oxide-assisted radio-immunotherapy

Radiotherapy is a crucial antineoplastic approach in clinical practice, but it often suffers from low therapeutic efficacy due to inadequate deposition of X-ray radiation and limited inhibition of metastatic tumors. Here, a bioinspired Hf-based metal-organic framework (Hf-MOF) nano-radiosensitizer (SHMR) is elaborately designed for boosting radio-immunotherapy by synergizing radio-sensitization with nitric oxide-assisted immune microenvironment remodeling. The engineered SHMR is constructed by wrapping RGD peptide-modified erythrocyte membrane onto sodium nitroprusside-loaded Hf-MOF. In vitro and in vivo experiments demonstrate that SHMR can induce immunogenic cell death and release abundant tumor-associated antigens to promote dendritic cells maturation and T cells activation under X-ray irradiation. Importantly, nitric oxide (NO) released from SHMR can not only relieve tumor hypoxia to alleviate radiotherapy resistance, but also reprogram tumor microenvironment, thereby reshaping the extracellular matrix barrier and enhancing immune cells infiltration. Specifically, SHMR in conjunction with αPD-L1 therapy exhibits favorable therapeutic outcomes in bilateral tumor and metastatic tumor models. This work creates a practical nano-radiosensitizer to achieve effective radiotherapy and NO-mediated tumor microenvironment reconstruction, providing a promising strategy for potentiating the radio-immunotherapy against “immune-cold” tumors.