Engineering a Tumor‐Targeted MgH ₂ @Lip/PD‐L1 Nanoplatform for Synergistic Hydrogen Therapy and Immune Activation

ABSTRACT Lung cancer remains the leading cause of cancer‐related deaths worldwide, yet immune checkpoint blockade (ICB) is often compromised by an immunosuppressive tumor microenvironment (TME) with acidosis, hypoxia, and poor T cell infiltration. Here, we develop a TME‐responsive nanoplatform (MgH 2 @Lip/PD‐L1) that couples hydrogen gas therapy with PD‐L1–targeted immunotherapy. The system features a hydrogen‐rich MgH 2 core, a pH‐sensitive liposomal shell, and PD‐L1 peptides for active targeting and checkpoint blockade. In acidic TME, MgH 2 @Lip/PD‐L1 generates H 2 and Mg(OH) 2 to neutralize acidity, elevate intracellular pH, disrupt mitochondrial membrane potential, and induce immunogenic cell death. In vivo, it achieves efficient tumor homing, suppresses tumor growth in both immunodeficient and immunocompetent models, and reprograms the TME by lowering Tregs and M2 macrophages while enhancing M1 polarization and CD3 + /CD45 + T cell infiltration. The platform also establishes durable immune memory against tumor rechallenge, functioning as an “immune gas factory” that converts “cold” tumors into “hot” tumors.