Spatiotemporally Controlled Co-Treatment of Lung Cancer and Pulmonary Immune-Related Adverse Events by Inhalable Albumin-Chaperoned Ultrathin MnO₂ Nanosheets

Cancer immunotherapy is often associated with immune-related adverse events (irAE), particularly in the lungs, which can lead to treatment discontinuation and negatively impact patient outcomes. In this study, we explore a spatiotemporally controlled cotreatment of lung cancer and pulmonary irAE using inhalable albumin-chaperoned ultrathin MnO₂ nanosheets (MnO₂@BSA). The MnO₂@BSA exhibits efficient reactive oxygen species scavenging and NIR-II photothermal properties. The inhalation route enhances MnO₂@BSA accumulation in the lungs and tumor tissue, offering localized treatment with reduced systemic toxicity. We demonstrate that ultrathin MnO₂@BSA nanosheets can inhibit the formation of neutrophil extracellular traps (NETs) by reducing reactive oxygen species (ROS) in neutrophils, thereby alleviating inflammation associated with irAE. In animal models, inhaled MnO₂@BSA reduced lung injury and inflammatory cell infiltration, while also decreasing pro-inflammatory cytokine levels, such as TNF-α, IL-1β, and IL-6. Simultaneously, MnO₂@BSA displays strong photothermal properties under 1064 nm laser irradiation, effectively ablating tumors. This photothermal therapy also induces immunogenic cell death (ICD), promoting the reuse of activated CD8+ T cells to enhance antitumor immunity. These dual effects─tumor destruction and irAE mitigation─highlight MnO₂@BSA's potential as a therapeutic platform for addressing the challenges of immunotherapy in lung cancer. We anticipate that this work could contribute to the development of inhalable metal-based nanomedicine for clinical transformation in tumor immunotherapy.