Local Delivery of Molecular Hydrogen by Fluorinated Zeolitic Imidazole Framework Nanosheets Boosts Cancer Immunotherapy

Identifying strategies to improve the efficacy of the immune checkpoint blockade (ICB) remains a major clinical need. Based on the high tissue penetration capability of hydrogen molecules (H 2 ) and their immunomodulatory effects, this work proposes a local gas delivery strategy targeting the tumor microenvironment for high-efficacy hydrogen immunotherapy. We synthesized hepta-fluorinated zeolitic imidazolate frameworks nanosheet (F 7 -ZIF) with high H 2 payload, sustained acid-responsive gas release property, and biodegradation. H 2 -loaded F 7 -ZIF (F 7 -ZIF/H 2 ) effectively released H 2 and Zn 2+ to induce significant mitochondrial damage and cell apoptosis. More importantly, F 7 -ZIF/H 2 considerably upregulated the expression of CD47 (“do not eat me” signal) on tumor cells, which increases target accessibility for anti-CD47 antibody, thereby enhancing their binding efficiency. RNA-seq suggests that the CD47 antibody not only blocks the “do not eat me” signal (mediated by CD47-SIRPα interactions) but also engages Fc receptors on macrophages through its Fc region to trigger antibody-dependent cellular phagocytosis. In melanoma tumor models with small (∼50 mm 3 ) and large sized established tumors (∼200 mm 3 ), the combination of F 7 -ZIF/H 2 and anti-CD47 reaches 90% and 83% of tumor inhibition rate, respectively, compared to free anti-CD47. When further combined with anti-PD-L1, the therapeutic system triggers systemic T cell immunity that rejects the progression of both primary and distal tumors. This work provides insights into gas-assisted cancer immunotherapy.